WO2024051670A1 - 结合tim-3的抗体与结合pd-1的抗体的药物组合 - Google Patents

结合tim-3的抗体与结合pd-1的抗体的药物组合 Download PDF

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WO2024051670A1
WO2024051670A1 PCT/CN2023/116907 CN2023116907W WO2024051670A1 WO 2024051670 A1 WO2024051670 A1 WO 2024051670A1 CN 2023116907 W CN2023116907 W CN 2023116907W WO 2024051670 A1 WO2024051670 A1 WO 2024051670A1
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Prior art keywords
antibody
antigen
binding fragment
tim
amino acid
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PCT/CN2023/116907
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English (en)
French (fr)
Inventor
桂在智
于鼎
王训强
袁亚妮
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正大天晴药业集团股份有限公司
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Publication of WO2024051670A1 publication Critical patent/WO2024051670A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present disclosure belongs to the field of biomedicine, and specifically relates to a pharmaceutical combination of an antibody that binds TIM-3 and an antibody that binds PD-1.
  • T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), also known as Hepatitis A Virus Cellular Receptor 2 (HAVCR2) , is a member of the TIM family of immunomodulatory proteins (the human TIM family includes TIM-1, 3, and 4).
  • TIM-3 is selectively expressed on the surface of activated Th1 cells, and is also expressed on myeloid cells, DC cells, NK cells, and macrophages. expressed on a variety of tumor cells.
  • TIM-3 has a variety of different ligands, including galectin 9 (Galectin9), phosphatidylserine (PtdSer), high mobility group protein B1 (HMGB1) and carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1).
  • Galectin9 galectin 9
  • PtdSer phosphatidylserine
  • HMGB1 high mobility group protein B1
  • CEACAM1 carcinoembryonic antigen cell adhesion molecule 1
  • TIM-3 As an immune checkpoint, TIM-3's physiological function is to negatively regulate the body's immune function and avoid damage to the body caused by excessive immunity or autoimmunity.
  • TIM-3 protein and/or mRNA is up-regulated on a variety of tumor tissues and tumor-related immune cells, participates in tumor immune evasion and immune response, and promotes tumor development.
  • PD-1 Programmed death-1, programmed death receptor 1
  • PD-L1 and PD-L2 Chinese patent document CN106977602A discloses an anti-PD-1 monoclonal antibody 14C12H1L1. This monoclonal antibody can effectively block the combination of PD-1 and PD-L1 and shows good anti-tumor activity.
  • Combining anti-TIM-3 antibodies with anti-PD-1 antibodies can jointly block the signaling pathways of TIM-3 and PD-1 and improve the anti-tumor effect.
  • the present disclosure provides a pharmaceutical combination comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof; optionally, a chemotherapeutic drug is also included.
  • the chemotherapeutic drug is a platinum-based anti-tumor drug and/or an antimetabolite anti-tumor drug.
  • the chemotherapeutic drug is a platinum-based antitumor drug and/or a cytosine-based antitumor drug.
  • the chemotherapeutic drugs are cisplatin and gemcitabine.
  • the pharmaceutical combination includes a unit dose of 60-1800 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof and a unit dose of 10-500 mg of an anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination includes a unit dose of 60-1800 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof, a unit dose of 10-500 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof, and a chemotherapy drug.
  • the pharmaceutical combination includes a unit dose of 60-1800 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof, a unit dose of 10-500 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof, and a unit dose of Cisplatin is 2.5-100 mg and gemcitabine is available in unit doses of 0.2-1.0 g.
  • the pharmaceutical combination includes 100-1800 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof and 10-800 mg of an anti-PD-1 antibody or antigen-binding fragment thereof.
  • the drug combination includes 100-1800 mg of anti-TIM-3 antibody or antigen-binding fragment thereof, 10-800 mg of anti-PD-1 antibody or antigen-binding fragment thereof, and a chemotherapeutic agent.
  • the pharmaceutical combination includes 100-1800 mg of anti-TIM-3 antibody or antigen-binding fragment thereof, 10-800 mg of anti-PD-1 antibody or antigen-binding fragment thereof, 40-80 mg/ m cisplatin and 0.5-1.0g/ m2 gemcitabine.
  • the pharmaceutical combination is suitable for administration in a single treatment cycle and includes 100-1800 mg of an anti-TIM-3 antibody. antibody or antigen-binding fragment thereof and 10-800 mg of anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle and includes 100-1800 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof, 10-800 mg of an anti-PD-1 antibody or antigen-binding fragment thereof and chemotherapy drugs.
  • the pharmaceutical combination is suitable for administration in a single treatment cycle and includes 100-1800 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof, 10-800 mg of an anti-PD-1 antibody or antigen-binding fragment thereof , 40-80 mg/m 2 of cisplatin and 1.0-2.0 g/m 2 of gemcitabine.
  • the pharmaceutical combination is used to treat tumors.
  • the present disclosure also provides a method of treating a tumor in a subject, comprising administering to the subject an effective amount of a pharmaceutical combination of the present disclosure.
  • the present disclosure also provides the use of the pharmaceutical combination of the present disclosure in the preparation of a medicament for treating tumors in a subject.
  • the present disclosure also provides the use of the pharmaceutical combination of the present disclosure in the preparation of a medicament for first-line treatment of tumors in a subject.
  • the present disclosure also provides the use of the pharmaceutical combination of the present disclosure to treat tumors in a subject.
  • the present disclosure also provides the use of the pharmaceutical combination of the present disclosure for first-line treatment of tumors in subjects.
  • the method or use includes administering to the subject an effective amount of a pharmaceutical combination of the present disclosure. In some embodiments, the method or use includes administering to the subject an effective amount of a pharmaceutical combination of the present disclosure in a first treatment phase, and administering to the subject an effective amount of the present disclosure in a second treatment phase. combination of drugs.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof can be administered simultaneously, sequentially, and/or alternately.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and the chemotherapeutic drug can be administered simultaneously, sequentially, and/or alternately.
  • the chemotherapeutic drug is a platinum-based anti-tumor drug and/or an antimetabolite anti-tumor drug.
  • the chemotherapeutic drug is a platinum-based antitumor drug and/or a cytosine-based antitumor drug.
  • the chemotherapeutic drugs are cisplatin and gemcitabine.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof is administered every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered at a dose of 100-1800 mg each time.
  • the anti-PD-1 antibody or antigen-binding fragment thereof is administered every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 10-800 mg per administration.
  • the cisplatin is administered every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, the cisplatin is administered at a dose of 40-80 mg/m per session.
  • the gemcitabine is administered twice every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, the gemcitabine is administered at a dose of 0.5-1.0 g/m per time.
  • kits for treating tumors comprising a pharmaceutical combination of the present disclosure.
  • the kit includes an anti-TIM-3 antibody or antigen-binding fragment thereof and an anti-PD-1 antibody or antigen-binding fragment thereof; optionally, a chemotherapeutic agent is also included.
  • the chemotherapeutic drug is a platinum-based anti-tumor drug and/or an antimetabolite anti-tumor drug.
  • the chemotherapeutic drug is a platinum-based anti-tumor drug and/or a cytosine-based anti-tumor drug.
  • the chemotherapeutic drugs are cisplatin and gemcitabine.
  • the present disclosure also provides anti-TIM-3 antibodies or antigen-binding fragments thereof for treating tumors.
  • the present disclosure also provides methods of treating tumors in a subject, comprising administering to the subject an effective amount of an anti-TIM-3 antibody or antigen-binding fragment thereof of the present disclosure.
  • the present disclosure also provides use of an anti-TIM-3 antibody, or antigen-binding fragment thereof, in the preparation of a medicament for treating a tumor in a subject.
  • the present disclosure also provides the use of anti-TIM-3 antibodies or antigen-binding fragments thereof to treat tumors.
  • the tumor is a solid tumor. In some embodiments, the tumor is nasopharyngeal carcinoma.
  • the present disclosure provides a pharmaceutical combination comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof; optionally, a chemotherapeutic drug is also included.
  • the chemotherapeutic drugs include, but are not limited to, platinum anti-tumor drugs, taxane anti-tumor drugs, antimetabolite anti-tumor drugs, camptothecin anti-tumor drugs, nitrogen mustard anti-tumor drugs, One or more of anthracycline anti-tumor drugs, vinblastine anti-tumor drugs, podophyllin alkaloid anti-tumor drugs, and hormonal anti-tumor drugs.
  • the chemotherapeutic drug is a platinum-based anti-tumor drug and/or an antimetabolite anti-tumor drug.
  • the chemotherapeutic drug is a platinum-based antitumor drug and/or a cytosine-based antitumor drug.
  • tumor drugs In some specific embodiments, the chemotherapeutic drugs are cisplatin and gemcitabine.
  • the pharmaceutical combination includes an anti-TIM-3 antibody, or antigen-binding fragment thereof, and an anti-PD-1 antibody, or antigen-binding fragment thereof.
  • the drug combination includes an anti-TIM-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, and a chemotherapeutic agent.
  • the drug combination includes an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof, a platinum-based anti-tumor drug, and an antimetabolite anti-tumor drug.
  • the drug combination includes an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof, a platinum-based antitumor drug, and a cytosine-based antitumor drug.
  • the pharmaceutical combination includes an anti-TIM-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, cisplatin, and gemcitabine.
  • a combined pharmaceutical combination which includes:
  • the combined pharmaceutical combination includes:
  • a pharmaceutical combination comprising an anti-TIM-3 antibody, or antigen-binding fragment thereof, and an anti-PD-1 antibody, or antigen-binding fragment thereof, prepared suitable for administration to the subject in the second treatment phase.
  • the combined pharmaceutical combination includes:
  • a drug combination including an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof, a platinum-based antineoplastic drug, and an antimetabolite antineoplastic drug, which is prepared to be suitable for use in the first administered to the subject during the treatment phase;
  • a pharmaceutical combination comprising an anti-TIM-3 antibody, or antigen-binding fragment thereof, and an anti-PD-1 antibody, or antigen-binding fragment thereof, prepared suitable for administration to the subject in the second treatment phase.
  • the combined pharmaceutical combination includes:
  • a pharmaceutical combination comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof, a platinum-based antitumor drug, and a cytosine-based antitumor drug, which is prepared to be suitable for use in the first administered to the subject during the treatment phase;
  • a pharmaceutical combination comprising an anti-TIM-3 antibody, or antigen-binding fragment thereof, and an anti-PD-1 antibody, or antigen-binding fragment thereof, prepared suitable for administration to the subject in the second treatment phase.
  • the combined pharmaceutical combination includes:
  • a pharmaceutical combination comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof, cisplatin and gemcitabine, prepared and adapted for administration to a subject during the first treatment phase;
  • a pharmaceutical combination comprising an anti-TIM-3 antibody, or antigen-binding fragment thereof, and an anti-PD-1 antibody, or antigen-binding fragment thereof, prepared suitable for administration to the subject in the second treatment phase.
  • the treatment cycles of the first treatment phase include 1-14 treatment cycles, preferably 2-12 treatment cycles, 2-10 treatment cycles, more preferably 2-8 treatment cycles, for example: 2 -8 treatment cycles, 3-8 treatment cycles, 4-8 treatment cycles, 2-7 treatment cycles, 3-7 treatment cycles, 4-7 treatment cycles, 2-6 treatment cycles, 3- 6 treatment cycles, or 4-6 treatment cycles; most preferably 4-6 treatment cycles, for example: 4 treatment cycles, 5 treatment cycles, and/or 6 treatment cycles.
  • a treatment cycle is every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, treatment cycles are every 3 weeks.
  • the second treatment phase follows the first treatment phase. In some embodiments, the second treatment phase is continued from the end of the first treatment phase until clinical benefit is lost, toxicity is intolerable, efficacy is assessed as progressive disease (PD), and/or the investigator deems it inappropriate to continue. Medication.
  • PD progressive disease
  • the pharmaceutical combination is packaged in the same kit, which further includes the combination of an anti-TIM-3 antibody or antigen-binding fragment thereof and an anti-PD-1 antibody or antigen-binding fragment thereof to treat tumors. instruction of.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical combination are separately packaged in respective kits, and the kit further includes Instructions for the combined use of anti-TIM-3 antibodies or antigen-binding fragments thereof and anti-PD-1 antibodies or antigen-binding fragments thereof to treat tumors.
  • the pharmaceutical combination is packaged in the same kit, which further includes an anti-TIM-3 antibody or antigen thereof Instructions for the combined use of binding fragments, anti-PD-1 antibodies, or antigen-binding fragments thereof, and chemotherapeutic agents (eg, cisplatin and gemcitabine) to treat tumors.
  • kit which further includes an anti-TIM-3 antibody or antigen thereof Instructions for the combined use of binding fragments, anti-PD-1 antibodies, or antigen-binding fragments thereof, and chemotherapeutic agents (eg, cisplatin and gemcitabine) to treat tumors.
  • chemotherapeutic agents eg, cisplatin and gemcitabine
  • the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and the chemotherapeutic drug (e.g., cisplatin and gemcitabine) in the pharmaceutical combination are packaged separately in respective
  • the kit also includes instructions for using an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof, and a chemotherapeutic drug (e.g., cisplatin and gemcitabine) in combination to treat tumors. .
  • the pharmaceutical combination is a fixed combination.
  • the fixed combination is in the form of a solid pharmaceutical composition or a liquid pharmaceutical composition.
  • the pharmaceutical combination is a non-fixed combination.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof in the non-fixed combination are each in the form of a pharmaceutical composition.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and the chemotherapeutic agent (e.g., cisplatin and gemcitabine) in the non-fixed combination are each in a pharmaceutical composition form.
  • the pharmaceutical composition containing the anti-TIM-3 antibody or antigen-binding fragment thereof in the non-fixed combination, is a liquid pharmaceutical composition or a solid pharmaceutical composition. In some specific embodiments, the pharmaceutical composition containing an anti-TIM-3 antibody or antigen-binding fragment thereof is an injection. In some specific embodiments, the pharmaceutical composition containing an anti-TIM-3 antibody or antigen-binding fragment thereof is a lyophilized preparation.
  • the pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof in the non-fixed combination, is a liquid pharmaceutical composition or a solid pharmaceutical composition. In some specific embodiments, the pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof is an injection. In some specific embodiments, the pharmaceutical composition containing an anti-PD-1 antibody or antigen-binding fragment thereof is a lyophilized preparation.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are formulated in a single formulation.
  • the pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof is a liquid pharmaceutical composition or a solid pharmaceutical composition.
  • the pharmaceutical composition containing an anti-TIM-3 antibody or antigen-binding fragment thereof and an anti-PD-1 antibody or antigen-binding fragment thereof is an injection.
  • the pharmaceutical composition containing an anti-TIM-3 antibody or antigen-binding fragment thereof and an anti-PD-1 antibody or antigen-binding fragment thereof is a lyophilized preparation.
  • the pharmaceutical composition containing the chemotherapeutic drug is a liquid pharmaceutical composition or a solid pharmaceutical composition.
  • the cisplatin-containing pharmaceutical composition is a liquid pharmaceutical composition or a solid pharmaceutical composition.
  • the gemcitabine-containing pharmaceutical composition is a liquid pharmaceutical composition or a solid pharmaceutical composition.
  • the cisplatin-containing pharmaceutical composition is an injection.
  • the gemcitabine-containing pharmaceutical composition is an injection.
  • the second container includes a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof; optionally, one or more other containers are also included, and the other containers include a pharmaceutical composition containing a chemotherapeutic drug (e.g., cis Platinum and gemcitabine) pharmaceutical compositions.
  • a chemotherapeutic drug e.g., cis Platinum and gemcitabine
  • the unit dosage of the anti-TIM-3 antibody or antigen-binding fragment thereof in the pharmaceutical combination is 60-1800 mg, 100-1600 mg, 120-1600 mg, 180-1200 mg, or 240-600 mg. In some embodiments, the unit dosage of the anti-TIM-3 antibody or antigen-binding fragment thereof in the pharmaceutical combination is about 60 mg, about 120 mg, about 160 mg, about 180 mg, about 200 mg, about 240 mg, about 280 mg, about 300 mg, about 320mg, about 360mg, about 400mg, about 420mg, about 440mg, about 480mg, about 520mg, about 540mg, about 560mg, about 600mg, about 640mg, about 660mg, about 680mg, about 720mg, about 760mg, about 780mg, about 800mg, About 840mg, about 880mg, about 900mg, about 920mg, about 960mg, about 1000mg, about 1020mg
  • the unit dosage of the anti-TIM-3 antibody or antigen-binding fragment thereof in the pharmaceutical combination is about 240 mg, about 300 mg, about 360 mg, and/or about 600 mg. In some embodiments, the unit dosage of the anti-TIM-3 antibody or antigen-binding fragment thereof in the pharmaceutical combination is about 240 mg and/or about 600 mg.
  • the unit dosage of the anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical combination is 10-500 mg, 50-500 mg, 50-200 mg, or 100-200 mg. In some embodiments, the unit dose of the anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical combination is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90mg, About 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg , about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 350
  • the unit dosage of the anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical combination is about 100 mg and/or about 200 mg. In some embodiments, the unit dose of the anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical combination is about 100 mg.
  • the pharmaceutical combination further includes a chemotherapeutic agent.
  • the chemotherapeutic drugs are cisplatin and gemcitabine.
  • the unit dose of cisplatin in the pharmaceutical combination is 2.5 mg, 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 50 mg and/or 100 mg.
  • the unit dose of gemcitabine in the pharmaceutical combination is 0.2 g and/or 1.0 g.
  • the pharmaceutical combination includes a unit dose of 60-1800 mg, 100-1600 mg, 120-1600 mg, 180-1200 mg, or 240-600 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof and a unit dose of 10 -500 mg, 50-500 mg, 50-200 mg, or 100-200 mg of anti-PD-1 antibody or antigen-binding fragment thereof.
  • the pharmaceutical combination includes a unit dose of about 60 mg, about 120 mg, about 160 mg, about 180 mg, about 200 mg, about 240 mg, about 280 mg, about 300 mg, about 320 mg, about 360 mg, about 400 mg, about 420 mg, About 440mg, about 480mg, about 520mg, about 540mg, about 560mg, about 600mg, about 640mg, about 660mg, about 680mg, about 720mg, about 760mg, about 780mg, about 800mg, about 840mg, about 880mg, about 900mg, about 920mg , about 960mg, about 1000mg, about 1020mg, about 1040mg, about 1080mg, about 1120mg, about 1140mg, about 1160mg, about 1200mg, about 1240mg, about 1260mg, about 1280mg, about 1320mg, about 1360mg, about 1380mg
  • TIM-3 antibody or antigen-binding fragment thereof and the unit dosage is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, About 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg , about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about
  • the pharmaceutical combination includes a unit dose of about 240 mg, about 300 mg, about 360 mg, and/or about 600 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof and a unit dose of about 100 mg and/or about 200 mg.
  • Anti-PD-1 antibody or antigen-binding fragment thereof In some embodiments, the pharmaceutical combination includes a unit dose of about 240 mg and/or about 600 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof and a unit dose of about 100 mg of an anti-PD-1 antibody or antigen-binding fragment thereof.
  • the pharmaceutical combination further includes cisplatin in unit doses of 2.5 mg, 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 50 mg and/or 100 mg and gemcitabine in unit doses of 0.2 g and/or 1.0 g. In some embodiments, the pharmaceutical combination further includes cisplatin in unit doses of 20 mg, 30 mg and/or 100 mg and gemcitabine in unit doses of 0.2 g and/or 1.0 g. In some embodiments, the pharmaceutical combination further includes cisplatin in a unit dose of 30 mg and gemcitabine in a unit dose of 0.2 g and/or 1.0 g.
  • the pharmaceutical combination includes an anti-TIM-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, cisplatin, and gemcitabine.
  • the pharmaceutical combination includes an anti-TIM-3 antibody or antigen-binding fragment thereof in a unit dose of about 240 mg, about 300 mg, about 360 mg, and/or about 600 mg, and a unit dose of about 100 mg and/or about 600 mg.
  • the pharmaceutical combination includes a unit dose of about 240 mg and/or about 600 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof, and a unit dose of about 100 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof fragments, cisplatin in unit doses of 20 mg, 30 mg and/or 100 mg, and gemcitabine in unit doses of 0.2 g and/or 1.0 g.
  • the pharmaceutical combination includes a unit dose of about 240 mg and/or about 600 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof, and a unit dose of about 100 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof fragment, cisplatin in unit doses of 30 mg, and gemcitabine in unit doses of 0.2 g and/or 1.0 g.
  • the pharmaceutical combination includes 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg Anti-TIM-3 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination includes about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, An anti-TIM-3 antibody or an antigen-binding fragment thereof in the range of about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg, or any of the above values. In some embodiments, the pharmaceutical combination includes about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination includes about 1200 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof.
  • the pharmaceutical combination includes 10-800 mg, 50-500 mg, or 100-200 mg of an anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination includes about 10 mg, about 50 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, An anti-PD-1 antibody or an antigen-binding fragment thereof in the range of about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, or any of the above values. In some embodiments, the pharmaceutical combination includes about 200 mg of an anti-PD-1 antibody or antigen-binding fragment thereof.
  • the pharmaceutical combination further includes a chemotherapeutic agent.
  • the chemotherapeutic drugs are cisplatin and gemcitabine.
  • the pharmaceutical combination further includes 40-80 mg/m 2 , or 40-75 mg/m 2 cisplatin.
  • the pharmaceutical combination further includes cisplatin in a range of 40 mg/m 2 , 60 mg/m 2 , 75 mg/m 2 , 80 mg/m 2 , or any of the above values.
  • the pharmaceutical combination further includes 40 mg/m 2 , 60 mg/m 2 or 75 mg/m 2 cisplatin.
  • the pharmaceutical combination further includes 75 mg/ m of cisplatin.
  • the pharmaceutical combination further includes 80 mg/ m of cisplatin. In some embodiments, the pharmaceutical combination further includes 0.5-1.0 g/ m of gemcitabine. In some embodiments, the pharmaceutical combination further includes gemcitabine in a range of 0.5 g/m 2 , 0.75 g/m 2 , 1.0 g/m 2 , or any of the above values. In some embodiments, the pharmaceutical combination further includes 0.5 g/m 2 , 0.75 g/m 2 or 1.0 g/m 2 gemcitabine. In some embodiments, the pharmaceutical combination further includes 1.0 g/m gemcitabine .
  • the pharmaceutical combination includes 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof, and 10-800 mg, 50-500 mg, or 100 -200 mg of anti-PD-1 antibody or antigen-binding fragment thereof.
  • the pharmaceutical combination includes about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, About 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg, or an anti-TIM-3 antibody or an antigen-binding fragment thereof within a range formed by any of the above values, and about 10 mg, about 50 mg, about 100 mg, about 120 mg, about 140 mg, About 160mg, about 180mg, about 200mg, about 220mg, about 240mg, about 260mg, about 280mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 550mg, about 600mg, about 650mg, about 700mg, about 750mg , or about 800 mg, or an anti-PD-1 antibody or an antigen-binding fragment thereof within a
  • the pharmaceutical combination includes about 1200 mg or about 1500 mg of an anti-TIM-3 antibody, or antigen-binding fragment thereof, and about 200 mg of an anti-PD-1 antibody, or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination includes about 1200 mg of an anti-TIM-3 antibody, or antigen-binding fragment thereof, and about 200 mg of an anti-PD-1 antibody, or antigen-binding fragment thereof.
  • the pharmaceutical combination further includes 40-80 mg/m 2 , or 40-75 mg/m 2 cisplatin, and 0.5-1.0 g/m 2 gemcitabine.
  • the pharmaceutical combination also includes cisplatin in the range of 40 mg/m 2 , 60 mg/m 2 , 75 mg/m 2 , 80 mg/m 2 , or any of the above values, and 0.5 g/m 2 , Gemcitabine in the range of 0.75g/m 2 , 1.0g/m 2 , or any of the above values.
  • the pharmaceutical combination further includes 75 mg/ m of cisplatin, and 1.0 g/ m of gemcitabine.
  • the pharmaceutical combination further includes 80 mg/ m of cisplatin, and 1.0 g/ m of gemcitabine.
  • the pharmaceutical combination includes an anti-TIM-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, cisplatin, and gemcitabine.
  • the pharmaceutical combination includes about 1200 mg or about 1500 mg of anti-TIM-3 antibody or antigen-binding fragment thereof, about 200 mg of anti-PD-1 antibody or antigen-binding fragment thereof, 40 mg/m 2 , 60 mg /m 2 , 75 mg/m 2 , or 80 mg/m 2 cisplatin, and 0.5 g/m 2 , 0.75 g/m 2 , or 1.0 g/m 2 gemcitabine.
  • the pharmaceutical combination includes about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof, about 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof, 75 mg/m of cis platinum, and gemcitabine at 1.0 g/ m2 .
  • the pharmaceutical combination includes about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof, about 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof, 80 mg/m 2 cisplatin, and gemcitabine at 1.0 g/ m2 .
  • the pharmaceutical combination includes about 1200 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof, about 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof, 75 mg/ m of cisplatin, and 1.0g/ m2 of gemcitabine.
  • the pharmaceutical combination contains an anti-TIM-3 antibody or antigen-binding fragment thereof in a daily dose. In some embodiments, the pharmaceutical combination contains the anti-TIM-3 antibody or antigen-binding fragment thereof in a once-daily dose.
  • the pharmaceutical combination contains a uniform dose of the anti-TIM-3 antibody or antigen-binding fragment thereof.
  • the amount of the anti-TIM-3 antibody or antigen-binding fragment thereof in the pharmaceutical combination is a dose for one treatment cycle, and each treatment cycle is 3 weeks.
  • the pharmaceutical combination contains a daily dose of the anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination contains the anti-PD-1 antibody or antigen-binding fragment thereof in a once-daily dose.
  • the pharmaceutical combination contains a uniform dose of the anti-PD-1 antibody or antigen-binding fragment thereof.
  • the pharmaceutical combination contains an anti-PD-1 antibody or an antigen-binding fragment thereof at a dose for one treatment cycle, and each treatment cycle is 3 weeks. In some embodiments, the pharmaceutical combination contains an anti-PD-1 antibody or an antigen-binding fragment thereof at a dose for one treatment cycle, and each treatment cycle is 2 weeks.
  • the pharmaceutical combination contains cisplatin in a daily dose. In some embodiments, the pharmaceutical combination contains cisplatin in a once-daily dose.
  • the pharmaceutical combination contains gemcitabine in a daily dose. In some embodiments, the pharmaceutical combination contains gemcitabine in a once-daily dose.
  • the pharmaceutical combination is suitable for administration in a single treatment cycle and includes 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof.
  • the pharmaceutical combination is suitable for administration in a single treatment cycle and includes about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg , about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg, or an anti-TIM-3 antibody or an antigen-binding fragment thereof within a range formed by any of the above values.
  • the pharmaceutical combination is suitable for administration in a single treatment cycle and includes about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle and includes about 1200 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof.
  • the pharmaceutical combination is suitable for administration in a single treatment cycle and includes 10-800 mg, 50-500 mg, or 100-200 mg of an anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle and includes about 10 mg, about 50 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg , about 260 mg, about 280 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, or about 800 mg, or the range formed by any of the above values.
  • PD-1 antibodies or antigen-binding fragments thereof the pharmaceutical combination is suitable for administration in a single treatment cycle and includes about 200 mg of an anti-PD-1 antibody or antigen-binding fragment thereof.
  • the drug combination is suitable for administration within a single treatment cycle and also includes a chemotherapeutic agent.
  • the chemotherapeutic drugs are cisplatin and gemcitabine.
  • the pharmaceutical combination is suitable for administration in a single treatment cycle and further includes 40-80 mg/m 2 , or 40-75 mg/m 2 cisplatin.
  • the pharmaceutical combination is suitable for administration within a single treatment cycle and also includes 40 mg/m 2 , 60 mg/m 2 , 75 mg/m 2 , 80 mg/m 2 , or a range formed by any of the above values. platinum.
  • the pharmaceutical combination is suitable for administration in a single treatment cycle and further includes 40 mg/m 2 , 60 mg/m 2 or 75 mg/m 2 cisplatin. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle and further includes 75 mg/ m of cisplatin. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle and further includes 80 mg/ m of cisplatin. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle and further includes 1.0-2.0 g/ m of gemcitabine.
  • the pharmaceutical combination is suitable for administration within a single treatment cycle and further includes 1.0 g/m 2 , 1.25 g/m 2 , 1.5 g/m 2 , 1.75 g/m 2 , 2.0 g/m 2 , or gemcitabine in the range formed by any of the above values.
  • the pharmaceutical combination is suitable for administration within a single treatment cycle and further includes 1.0 g/m 2 , 1.25 g/m 2 , 1.5 g/m 2 , 1.75 g/m 2 , 2.0 g/m 2 of gemcitabine.
  • the pharmaceutical combination is suitable for administration in a single treatment cycle and further includes 2.0 g/m of gemcitabine .
  • the pharmaceutical combination is suitable for administration within a single treatment cycle and includes an anti-TIM-3 antibody, or antigen-binding fragment thereof, and an anti-PD-1 antibody, or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle and includes 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof, and 10-800 mg, 50-500 mg, or 100-200 mg of an anti-PD-1 antibody or antigen-binding fragment thereof.
  • the pharmaceutical combination is suitable for administration in a single treatment cycle and includes about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg , about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg, or an anti-TIM-3 antibody or an antigen-binding fragment thereof within a range formed by any of the above values, and about 10 mg, about 50 mg , about 100mg, about 120mg, about 140mg, about 160mg, about 180mg, about 200mg, about 220mg, about 240mg, about 260mg, about 280mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 550mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, or about 800 mg, or an anti-PD-1 antibody or
  • the pharmaceutical combination is suitable for administration in a single treatment cycle and includes about 1200 mg or about 1500 mg of an anti-TIM-3 antibody, or antigen-binding fragment thereof, and about 200 mg of an anti-PD-1 antibody, or antigen-binding fragment thereof. fragment. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle and includes about 1200 mg of an anti-TIM-3 antibody, or antigen-binding fragment thereof, and about 200 mg of an anti-PD-1 antibody, or antigen-binding fragment thereof.
  • the pharmaceutical combination is suitable for administration in a single treatment cycle and further includes 40-80 mg/m 2 , or 40-75 mg/m 2 cisplatin, and 1.0-2.0 g/m 2 gemcitabine.
  • the pharmaceutical combination is suitable for administration within a single treatment cycle and also includes 40 mg/m 2 , 60 mg/m 2 , 75 mg/m 2 , 80 mg/m 2 , or a range formed by any of the above values.
  • Platinum, and gemcitabine in the range of 1.0g/m 2 , 1.25g/m 2 , 1.5g/m 2 , 1.75g/m 2 , 2.0g/m 2 , or any of the above values.
  • the pharmaceutical combination is suitable for administration in a single treatment cycle and further includes 75 mg/ m of cisplatin, and 2.0 g/m of gemcitabine. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle and further includes 80 mg/ m of cisplatin, and 2.0 g/m of gemcitabine.
  • the pharmaceutical combination is suitable for administration in a single treatment cycle and includes an anti-TIM-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, cisplatin, and gemcitabine.
  • the pharmaceutical combination is suitable for administration in a single treatment cycle and includes about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof, and about 200 mg of an anti-PD-1 antibody or antigen-binding fragment thereof.
  • the pharmaceutical combination is suitable for administration in a single treatment cycle and includes about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof, and about 200 mg of an anti-PD-1 antibody or antigen-binding fragment thereof.
  • the pharmaceutical combination is suitable for administration in a single treatment cycle and includes about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof, about 200 mg of an anti-PD-1 antibody or Its antigen-binding fragment, cisplatin at 80mg/ m2 , and gemcitabine at 2.0g/ m2 .
  • the pharmaceutical combination is suitable for administration in a single treatment cycle and includes about 1200 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof and about 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof. , cisplatin at 75mg/ m2 , and gemcitabine at 2.0g/ m2 .
  • the combination drug combination provided by the present disclosure includes:
  • the combination drug combination provided by the present disclosure includes:
  • a pharmaceutical combination comprising about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof and about 200 mg of an anti-PD-1 antibody or antigen-binding fragment thereof, prepared as a single treatment in the second treatment phase cycles were administered to subjects.
  • the combination drug combination provided by the present disclosure includes:
  • (a) includes about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof, about 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof, 75 mg/ m of cisplatin, and 2.0 g/m of Gemcitabine pharmaceutical combinations prepared to be suitable during the first phase of treatment A single treatment cycle is administered to the subject; and
  • a pharmaceutical combination comprising about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof and about 200 mg of an anti-PD-1 antibody or antigen-binding fragment thereof, prepared as a single treatment in the second treatment phase cycles were administered to subjects.
  • the combination drug combination provided by the present disclosure includes:
  • (a) includes about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof, about 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof, 80 mg/ m of cisplatin, and 2.0 g/m of A pharmaceutical combination of gemcitabine formulated for administration to a subject in a single treatment cycle of the first treatment phase; and
  • a pharmaceutical combination comprising about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof and about 200 mg of an anti-PD-1 antibody or antigen-binding fragment thereof, prepared as a single treatment in the second treatment phase cycles were administered to subjects.
  • the combination drug combination provided by the present disclosure includes:
  • a drug comprising approximately 1200 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof, approximately 200 mg of an anti-PD-1 antibody or antigen-binding fragment thereof, 75 mg/ m of cisplatin, and 2.0 g/m of gemcitabine A combination prepared for administration to a subject in a single treatment cycle of the first treatment phase;
  • a pharmaceutical combination comprising about 1200 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof and about 200 mg of an anti-PD-1 antibody or antigen-binding fragment thereof, formulated to be suitable for administration to a subject in a single treatment cycle of the second treatment phase; Give to the tester.
  • the treatment cycles of the first treatment phase include 1-14 treatment cycles, preferably 2-12 treatment cycles, 2-10 treatment cycles, more preferably 2-8 treatment cycles, for example: 2 -8 treatment cycles, 3-8 treatment cycles, 4-8 treatment cycles, 2-7 treatment cycles, 3-7 treatment cycles, 4-7 treatment cycles, 2-6 treatment cycles, 3- 6 treatment cycles, or 4-6 treatment cycles; most preferably 4-6 treatment cycles, for example: 4 treatment cycles, 5 treatment cycles, and/or 6 treatment cycles.
  • the second treatment phase follows the first treatment phase. In some embodiments, the second treatment phase is continued from the end of the first treatment phase until clinical benefit is lost, toxicity is intolerable, efficacy is assessed as PD, and/or the investigator deems it inappropriate to continue treatment.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof can be a pharmaceutical composition containing an anti-TIM-3 antibody or antigen-binding fragment thereof.
  • the pharmaceutical composition containing anti-TIM-3 antibody or antigen-binding fragment thereof is a single dose or multiple doses, preferably multiple doses.
  • the multiple doses may consist of a single dose of a pharmaceutical composition containing about 240 mg, about 300 mg, about 360 mg, and/or about 600 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof.
  • the multiple doses may consist of a single dose of a pharmaceutical composition containing about 240 mg and/or about 600 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof.
  • the anti-PD-1 antibody or antigen-binding fragment thereof may be a pharmaceutical composition containing an anti-PD-1 antibody or antigen-binding fragment thereof.
  • the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is a single dose or multiple doses, preferably multiple doses.
  • the multiple doses may consist of a single dose of a pharmaceutical composition containing about 100 mg and/or about 200 mg of an anti-PD-1 antibody or antigen-binding fragment thereof.
  • the multiple doses can consist of a single dose of a pharmaceutical composition containing about 100 mg of an anti-PD-1 antibody or antigen-binding fragment thereof.
  • the chemotherapeutic agent may be a pharmaceutical composition containing a chemotherapeutic agent.
  • the pharmaceutical composition containing chemotherapeutic drugs is a single dose or multiple doses, preferably multiple doses.
  • the chemotherapeutic drugs are cisplatin and gemcitabine.
  • the cisplatin can be a cisplatin-containing pharmaceutical composition.
  • the pharmaceutical composition containing cisplatin is a single dose or multiple doses, preferably multiple doses.
  • the multiple doses may consist of a single dose of a pharmaceutical composition containing 2.5 mg, 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 50 mg, and/or 100 mg of cisplatin.
  • the multiple doses may consist of a single dose of a pharmaceutical composition containing 30 mg of cisplatin.
  • the gemcitabine may be a gemcitabine-containing pharmaceutical composition.
  • the pharmaceutical composition containing gemcitabine is a single dose or multiple doses, preferably multiple doses.
  • the multiple doses may consist of a single dose of a pharmaceutical composition containing 0.2 g and/or 1.0 g gemcitabine.
  • the mass ratio of the anti-TIM-3 antibody or antigen-binding fragment thereof: anti-PD-1 antibody or antigen-binding fragment thereof is (0.1-180):1, (0.2- 50):1, (0.5-9):1, (3-7.5):1, (4-7.5):1 or (6-7.5):1; wherein, the anti-TIM-3 antibody or antigen-binding fragment thereof and Anti-PD-1 antibodies or antigen-binding fragments thereof may be packaged separately or together. And among them, the anti-TIM-3 antibody or its antigen-binding fragment can be packaged in single or multiple portions, and the anti-PD-1 antibody or its antigen-binding fragment can be packaged in single or multiple portions.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof can be administered in single or multiple aliquots (e.g., 2 aliquots, 3 aliquots, 4 aliquots, 5 aliquots, 6 aliquots, 7 aliquots , 8 or more aliquots), anti-PD-1 antibodies or antigen-binding fragments thereof can be packaged in single Packaging in one or more equal parts (such as 2 equal parts or other equal parts).
  • the pharmaceutical combination includes a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof and a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the anti-TIM-3 antibody is or an antigen-binding fragment thereof, a pharmaceutical composition prepared as a single or multiple dose suitable for administration to a patient of 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof, containing
  • the pharmaceutical composition of the anti-PD-1 antibody or antigen-binding fragment thereof is prepared as a single or multiple dose suitable for administration to a patient of 10-800 mg, 50-500 mg, or 100-200 mg of the anti-PD-1 antibody or antigen-binding fragment thereof.
  • the pharmaceutical combination includes a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof and a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the anti-TIM-3 antibody is or an antigen-binding fragment thereof, a pharmaceutical composition prepared suitable for administration to a patient of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about A single dose or multiple doses of an anti-TIM-3 antibody or antigen-binding fragment thereof, containing 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg, or a range formed by any of the above values, containing anti-PD- 1
  • the pharmaceutical composition of the antibody or antigen-binding fragment thereof is prepared to be suitable for administration to a patient of about 10 mg, about 50 mg, about 100 mg, about 120 mg, about 140 mg, about
  • the pharmaceutical combination includes a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof and a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the anti-TIM-3 antibody is or an antigen-binding fragment thereof, a pharmaceutical composition prepared as a single or multiple dose suitable for administering to a patient about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof, containing an anti-PD-1 antibody or an antigen-binding fragment thereof
  • the pharmaceutical composition is formulated to be suitable for administration to a patient in a single or multiple dose of about 200 mg of an anti-PD-1 antibody or antigen-binding fragment thereof.
  • the pharmaceutical combination includes a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof and a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the anti-TIM-3 antibody is or an antigen-binding fragment thereof, a pharmaceutical composition prepared as a single dose or multiple doses suitable for administering to a patient about 1200 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof, a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof Prepared as a single or multiple dose suitable for administration to a patient of about 200 mg of an anti-PD-1 antibody or antigen-binding fragment thereof.
  • the pharmaceutical combination further includes a chemotherapeutic agent.
  • the chemotherapeutic drugs are cisplatin and gemcitabine.
  • the pharmaceutical combination further includes a cisplatin-containing pharmaceutical composition and a gemcitabine-containing pharmaceutical composition, wherein the cisplatin-containing pharmaceutical composition is formulated to be suitable for administration to the patient at 40-80 mg/m 2 , or Single or multiple doses of 40-75 mg/ m cisplatin, gemcitabine-containing pharmaceutical compositions are prepared suitable for administering to patients single or multiple doses of 0.5-1.0 g/m 2 gemcitabine.
  • the pharmaceutical combination further includes a cisplatin-containing pharmaceutical composition and a gemcitabine-containing pharmaceutical composition
  • the cisplatin-containing pharmaceutical composition is prepared suitable for administration to the patient at 40 mg/m 2 , 60 mg/m 2 , 75 mg/m 2 , 80 mg/m 2 , or a single dose or multiple doses of cisplatin in the range formed by any of the above values
  • the pharmaceutical composition containing gemcitabine is prepared to be suitable for administration to the patient at 0.5 g/m 2 , 0.75 g /m 2 , 1.0 g/m 2 , or a single dose or multiple doses of gemcitabine in the range formed by any of the above values.
  • the pharmaceutical combination further includes a cisplatin-containing pharmaceutical composition and a gemcitabine-containing pharmaceutical composition, wherein the cisplatin-containing pharmaceutical composition is prepared as a single dose of cisplatin at 75 mg/ m2 .
  • pharmaceutical compositions containing gemcitabine are prepared as a single dose or multiple doses suitable for administration to a patient of 1.0 g/ m2 of gemcitabine.
  • the pharmaceutical combination further includes a cisplatin-containing pharmaceutical composition and a gemcitabine-containing pharmaceutical composition, wherein the cisplatin-containing pharmaceutical composition is prepared as a single dose of cisplatin at 80 mg/ m2 suitable for administration to the patient.
  • pharmaceutical compositions containing gemcitabine are prepared as a single dose or multiple doses suitable for administration to a patient of 1.0 g/ m2 of gemcitabine.
  • the pharmaceutical combination includes a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof, a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof, a pharmaceutical composition containing cisplatin , and pharmaceutical compositions containing gemcitabine.
  • the pharmaceutical composition comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof is formulated to be suitable for administering to a patient about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof.
  • a single dose or multiple doses of a fragment, a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof is prepared that is suitable for administering to a patient a single dose or multiple doses of about 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof, containing
  • the pharmaceutical composition of cisplatin is prepared as a single dose or multiple doses suitable for administering 40 mg/m 2 , 60 mg/m 2 , 75 mg/m 2 or 80 mg/m 2 cisplatin to a patient, and the pharmaceutical composition containing gemcitabine is prepared as It is suitable to administer single or multiple doses of gemcitabine at 0.5g/ m2 , 0.75g/ m2 or 1.0g/ m2 to patients.
  • the pharmaceutical composition comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof is formulated to be suitable for administering to a patient about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof.
  • a single dose or multiple doses of a fragment, a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof is prepared suitable for administering to a patient about 200 mg of an anti-PD-1 antibody.
  • the pharmaceutical composition containing cisplatin is prepared to be suitable for administering to a patient a single or multiple doses of 75 mg/m 2 cisplatin
  • the pharmaceutical composition containing gemcitabine is prepared to be suitable for administration to a patient Patients were administered single or multiple doses of 1.0 g/ m2 gemcitabine.
  • the pharmaceutical composition comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof is formulated to be suitable for administering to a patient about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof.
  • a single dose or multiple doses of a fragment, a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof is prepared that is suitable for administering to a patient a single dose or multiple doses of about 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof, containing
  • the pharmaceutical composition of cisplatin is prepared as a single dose or multiple doses of 80 mg/ m of cisplatin
  • the pharmaceutical composition containing gemcitabine is prepared as a single or multiple dose of 1.0 g/ m of gemcitabine. dose.
  • the pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof is prepared as a single dose suitable for administering to a patient about 1200 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof.
  • a dose or multiple doses of a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof is formulated to be suitable for administering to a patient a single dose or multiple doses of about 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof, containing cisplatin.
  • the pharmaceutical compositions are prepared as a single dose or multiple doses of 75 mg/ m cisplatin and the pharmaceutical compositions containing gemcitabine are prepared as a single or multiple doses of 1.0 g/ m gemcitabine.
  • the pharmaceutical combination includes a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof and a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the anti-TIM-3 antibody is
  • the pharmaceutical composition of the anti-TIM-3 antibody or the antigen-binding fragment thereof is prepared to be suitable for administering to the patient at the first administration 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg of a single anti-TIM-3 antibody or antigen-binding fragment thereof.
  • a dose or multiple doses a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof is prepared to administer to a patient 10-800 mg, 50-500 mg, or 100-200 mg of an anti-PD-1 antibody at the first administration or single or multiple doses of antigen-binding fragments thereof.
  • the pharmaceutical combination includes a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof and a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the anti-TIM-3 antibody is or an antigen-binding fragment thereof, a pharmaceutical composition prepared suitable for administering to a patient at a first administration about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about A single or multiple doses of an anti-TIM-3 antibody or an antigen-binding fragment thereof of 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg, or a range formed by any of the above values.
  • a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof is prepared for administration to a patient at a first administration of about 10 mg, about 50 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg , about 200mg, about 220mg, about 240mg, about 260mg, about 280mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 550mg, about 600mg, about 650mg, about 700mg, about 750mg, or about 800mg, Or a single dose or multiple doses of an anti-PD-1 antibody or an antigen-binding fragment thereof within a range formed by any of the above values.
  • the pharmaceutical combination includes a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof and a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the anti-TIM-3 antibody is or an antigen-binding fragment thereof, a pharmaceutical composition prepared suitable for administering to a patient for the first time a single or multiple dose of about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof, containing an anti-PD-1 antibody or an antigen-binding fragment thereof, is formulated to be suitable for administering to a patient a single or multiple dose of about 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof at the first administration.
  • the pharmaceutical combination includes a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof and a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the anti-TIM-3 antibody is or an antigen-binding fragment thereof, a pharmaceutical composition prepared suitable for administering to a patient a single or multiple dose of about 1200 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof, containing an anti-PD-1 antibody or an antigen thereof, for the first time
  • the pharmaceutical composition of the binding fragment is formulated to be suitable for administering to a patient a single or multiple dose of about 200 mg of the anti-PD-1 antibody or antigen-binding fragment thereof upon first administration.
  • the pharmaceutical combination further includes a chemotherapeutic agent.
  • the chemotherapeutic drugs are cisplatin and gemcitabine.
  • the pharmaceutical combination further includes a cisplatin-containing pharmaceutical composition and a gemcitabine-containing pharmaceutical composition, wherein the cisplatin-containing pharmaceutical composition is formulated to be administered to the patient for 40- A single dose or multiple doses of 80 mg/m 2 , or 40-75 mg/m 2 cisplatin, the pharmaceutical composition containing gemcitabine is prepared to be suitable for administering a single dose of 0.5-1.0 g/m 2 gemcitabine to the patient every week for two consecutive weeks. dose or multiple doses.
  • the pharmaceutical combination further includes a cisplatin-containing pharmaceutical composition and a gemcitabine-containing pharmaceutical composition, wherein the cisplatin-containing pharmaceutical composition is prepared to be administered to the patient at the first administration of 40 mg/ m 2 , 60 mg/m 2 , 75 mg/m 2 , 80 mg/m 2 , or a single dose or multiple doses of cisplatin in the range formed by any of the above values, the pharmaceutical composition containing gemcitabine is prepared to be suitable for two consecutive weeks, every day. Single or multiple doses of gemcitabine in a range of 0.5 g/m 2 , 0.75 g/m 2 , 1.0 g/m 2 , or any of the above values are administered to the patient.
  • the pharmaceutical combination further includes a cisplatin-containing pharmaceutical composition and a gemcitabine-containing pharmaceutical composition, wherein the cisplatin-containing pharmaceutical composition is formulated to be administered to the patient at the first administration of 75 mg/ m 2 cisplatin single or multiple doses, gemcitabine-containing pharmaceutical compositions are formulated to be suitable for administering single or multiple doses of 1.0 g/m 2 gemcitabine to a patient every week for two consecutive weeks.
  • the pharmaceutical combination also includes a cisplatin-containing pharmaceutical composition and a gemcitabine-containing pharmaceutical composition, wherein the cisplatin-containing pharmaceutical composition is prepared to be suitable for administering a single dose of 80 mg/m cisplatin to the patient during the first administration.
  • the pharmaceutical composition containing gemcitabine is formulated to be suitable for administering to a patient a single dose or multiple doses of 1.0 g/ m2 gemcitabine every week for two consecutive weeks.
  • the pharmaceutical combination includes a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof, a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof, a pharmaceutical composition containing cisplatin , and pharmaceutical compositions containing gemcitabine.
  • the pharmaceutical composition containing an anti-TIM-3 antibody or antigen-binding fragment thereof is prepared to administer to the patient at the first administration about 1200 mg or about 1500 mg of anti-TIM-3 antibody or an antigen-binding fragment thereof.
  • the pharmaceutical composition containing the anti-PD-1 antibody or the antigen-binding fragment thereof is prepared to be suitable for administering to the patient about 200 mg of the anti-PD-1 antibody or Single or multiple doses of antigen-binding fragments thereof
  • cisplatin-containing pharmaceutical compositions are prepared suitable for administration to a patient at a first administration of 40 mg/m 2 , 60 mg/m 2 , 75 mg/m 2 or 80 mg/m 2
  • pharmaceutical compositions containing gemcitabine are formulated to be suitable for administering to patients a single dose or multiple doses of 0.5 g/m 2 , 0.75 g/m 2 or 1.0 g/m 2 gemcitabine every week for two consecutive weeks.
  • the pharmaceutical composition containing an anti-TIM-3 antibody or antigen-binding fragment thereof is prepared to administer to the patient at the first administration about 1200 mg or about 1500 mg of anti-TIM-3 antibody or an antigen-binding fragment thereof.
  • the pharmaceutical composition containing the anti-PD-1 antibody or the antigen-binding fragment thereof is prepared to be suitable for administering to the patient about 200 mg of the anti-PD-1 antibody or
  • a single or multiple dose, cisplatin-containing pharmaceutical composition of the antigen-binding fragment thereof is formulated to be suitable for administering to a patient a single or multiple dose, gemcitabine-containing pharmaceutical composition of 75 mg/m 2 cisplatin at the first administration Formulated to be suitable for administration to patients as single or multiple doses of 1.0 g/ m2 gemcitabine weekly for two consecutive weeks.
  • the pharmaceutical composition containing an anti-TIM-3 antibody or antigen-binding fragment thereof is prepared to administer to the patient at the first administration about 1200 mg or about 1500 mg of anti-TIM-3 antibody or an antigen-binding fragment thereof.
  • the pharmaceutical composition containing the anti-PD-1 antibody or the antigen-binding fragment thereof is prepared to be suitable for administering to the patient about 200 mg of the anti-PD-1 antibody or
  • a single or multiple dose, cisplatin-containing pharmaceutical composition of the antigen-binding fragment thereof is formulated to be suitable for administering to a patient a single or multiple dose, gemcitabine-containing pharmaceutical composition of 80 mg/m 2 cisplatin at the first administration Formulated to be suitable for administration to patients as single or multiple doses of 1.0 g/ m2 gemcitabine weekly for two consecutive weeks.
  • the pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof is prepared to administer to the patient for the first time about 1200 mg of the anti-TIM-3 antibody or A single dose or multiple doses of an antigen-binding fragment thereof, a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof is prepared suitable for administering to a patient at the first administration approximately 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof Single or multiple doses of fragments, cisplatin-containing pharmaceutical compositions are formulated to be suitable for administering single or multiple doses of 75 mg/m 2 cisplatin to a patient at the first dose, gemcitabine-containing pharmaceutical compositions are formulated as It is suitable to administer single or multiple doses of gemcitabine 1.0 g/ m2 to patients every week for two consecutive weeks.
  • the present disclosure provides a kit for treating tumors, the kit comprising a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof and a medicament containing an anti-PD-1 antibody or an antigen-binding fragment thereof.
  • the kit includes a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof, a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof, and a pharmaceutical composition containing a chemotherapeutic agent. and instructions for combining a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof, a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof, and a pharmaceutical composition containing a chemotherapeutic drug to treat tumors.
  • the chemotherapeutic drug is a platinum-based anti-tumor drug and/or an antimetabolite anti-tumor drug.
  • the chemotherapeutic drug is a platinum-based antitumor drug and/or a cytosine-based antitumor drug.
  • the chemotherapeutic drugs are cisplatin and gemcitabine.
  • the kit includes a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof, a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof, a cisplatin-containing medicine Compositions and pharmaceutical compositions containing gemcitabine, and pharmaceutical compositions containing anti-TIM-3 antibodies or antigen-binding fragments thereof, pharmaceutical compositions containing anti-PD-1 antibodies or antigen-binding fragments thereof, and pharmaceutical compositions containing cisplatin Instructions for the combined use of pharmaceutical compositions containing gemcitabine and gemcitabine for the treatment of tumors.
  • the present disclosure provides a kit for treating tumors, the kit comprising a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof, and using Instructions for treating tumors with a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof.
  • the kit includes a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof, and a pharmaceutical composition containing a chemotherapeutic agent, and Description of the combined use of a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof, and a pharmaceutical composition containing a chemotherapeutic drug to treat tumors.
  • the chemotherapeutic drug is a platinum-based anti-tumor drug and/or an antimetabolite anti-tumor drug.
  • the chemotherapeutic agent It is a platinum-based antitumor drug and/or a cytosine-based antitumor drug.
  • the chemotherapeutic drugs are cisplatin and gemcitabine.
  • the kit includes a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof, a pharmaceutical composition containing cisplatin, and a pharmaceutical composition containing gemcitabine.
  • the pharmaceutical composition and the combined use of a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof, a pharmaceutical composition containing cisplatin, and a pharmaceutical composition containing gemcitabine Instructions for treating tumors.
  • the present disclosure also provides a pharmaceutical package for treating tumors, which contains individually packaged pharmaceutical compositions in separate containers, wherein the first container includes an anti-TIM-3 antibody or an antigen thereof.
  • a pharmaceutical composition for binding fragments including in a second container a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof; optionally, also containing one or more other containers, including chemotherapy containing Pharmaceutical compositions of drugs.
  • the chemotherapeutic drug is a platinum-based anti-tumor drug and/or an antimetabolite anti-tumor drug.
  • the chemotherapeutic drug is a platinum-based antitumor drug and/or a cytosine-based antitumor drug.
  • the chemotherapeutic drugs are cisplatin and gemcitabine.
  • the pharmaceutical package contains individually packaged pharmaceutical compositions in separate containers, wherein a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof is included in the first container, and a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof in a second container.
  • the pharmaceutical package contains individually packaged pharmaceutical compositions in separate containers, wherein a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof is included in the first container, Included in a second container is a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof, in a third container a pharmaceutical composition containing cisplatin, and in a fourth container a pharmaceutical composition containing gemcitabine combination.
  • the present disclosure also provides a pharmaceutical package for treating tumors, which contains individually packaged pharmaceutical compositions in separate containers, wherein the first container includes an anti-TIM-3 antibody or an antigen thereof.
  • the chemotherapeutic drug is a platinum-based anti-tumor drug and/or an antimetabolite anti-tumor drug.
  • the chemotherapeutic drug is a platinum-based antitumor drug and/or a cytosine-based antitumor drug.
  • the chemotherapeutic drugs are cisplatin and gemcitabine.
  • the drug package contains individually packaged pharmaceutical compositions in separate containers, wherein the first container includes an anti-TIM-3 antibody or antigen-binding fragment thereof and an anti-PD-1 Pharmaceutical compositions of antibodies or antigen-binding fragments thereof.
  • the drug package contains individually packaged pharmaceutical compositions in separate containers, wherein the first container includes an anti-TIM-3 antibody or antigen-binding fragment thereof and an anti-PD-1 A pharmaceutical composition of an antibody or an antigen-binding fragment thereof, comprising a pharmaceutical composition containing cisplatin in a second container and a pharmaceutical composition containing gemcitabine in a third container.
  • the pharmaceutical composition containing the anti-TIM-3 antibody or antigen-binding fragment thereof is a liquid pharmaceutical composition or a solid pharmaceutical composition.
  • the pharmaceutical composition containing an anti-TIM-3 antibody or antigen-binding fragment thereof is an injection.
  • the pharmaceutical composition containing an anti-TIM-3 antibody or antigen-binding fragment thereof is a lyophilized preparation.
  • the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is a liquid pharmaceutical composition or a solid pharmaceutical composition.
  • the pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof is an injection.
  • the pharmaceutical composition containing an anti-PD-1 antibody or antigen-binding fragment thereof is a lyophilized preparation.
  • the pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof is a liquid pharmaceutical composition or a solid pharmaceutical. combination.
  • the pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof is an injection.
  • the pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof is a lyophilized preparation.
  • the pharmaceutical composition containing the chemotherapeutic drug is a liquid pharmaceutical composition or a solid pharmaceutical composition.
  • the pharmaceutical composition containing cisplatin is a liquid pharmaceutical composition or a solid pharmaceutical composition.
  • the pharmaceutical composition containing gemcitabine is a liquid pharmaceutical composition or a solid pharmaceutical composition.
  • the cisplatin-containing pharmaceutical composition is an injection.
  • the gemcitabine-containing pharmaceutical composition is an injection.
  • the cisplatin-containing pharmaceutical composition is a powder.
  • the gemcitabine-containing pharmaceutical composition is a powder.
  • the tumor is a solid tumor. In some embodiments, the solid tumor is nasopharyngeal carcinoma.
  • the present disclosure also provides methods of treating tumors in a subject, comprising administering to the subject an effective amount of a pharmaceutical combination of the present disclosure.
  • the present disclosure also provides the use of the pharmaceutical combination of the present disclosure for first-line treatment of tumors in subjects.
  • the present disclosure also provides use of a pharmaceutical combination of the present disclosure for the preparation of a medicament for treating a tumor in a subject.
  • the present disclosure also provides the use of the pharmaceutical combination of the present disclosure in the preparation of a medicament for first-line treatment of tumors in a subject.
  • the pharmaceutical combination in the method or use, includes an anti-TIM-3 antibody, or antigen-binding fragment thereof, and an anti-PD-1 antibody, or antigen-binding fragment thereof.
  • the pharmaceutical combination includes an anti-TIM-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, and a chemotherapeutic agent.
  • the chemotherapeutic drugs include, but are not limited to, platinum anti-tumor drugs, taxane anti-tumor drugs, antimetabolite anti-tumor drugs, camptothecin anti-tumor drugs, nitrogen mustard anti-tumor drugs, One or more of anthracycline anti-tumor drugs, vinblastine anti-tumor drugs, podophyllin alkaloid anti-tumor drugs, and hormonal anti-tumor drugs.
  • the chemotherapeutic drug is a platinum-based anti-tumor drug and/or an antimetabolite anti-tumor drug. In some embodiments, the chemotherapeutic drug is a platinum-based antitumor drug and/or a cytosine-based antitumor drug. In some specific embodiments, the chemotherapeutic drugs are cisplatin and gemcitabine. In some embodiments, in the method or use, the drug combination includes an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof, a platinum-based antineoplastic drug, and an antimetabolite. Antineoplastic drugs.
  • the drug combination includes an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof, a platinum-based antineoplastic drug, and a cytosine-based Antineoplastic drugs.
  • the pharmaceutical combination includes an anti-TIM-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, cisplatin, and gemcitabine.
  • the present disclosure also provides the use of an anti-TIM-3 antibody or an antigen-binding fragment thereof in the preparation of a medicament for treating a tumor in a subject, wherein the medicament is for use in combination with an anti-PD-1 antibody antigen-binding fragment of the present disclosure.
  • the present disclosure also provides the use of an anti-TIM-3 antibody or an antigen-binding fragment thereof in the preparation of a medicament for treating a tumor in a subject, wherein the medicament is used with an anti-PD-1 antibody antigen-binding fragment of the present disclosure and chemotherapy. Combined use of drugs.
  • the present disclosure also provides the use of an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody antigen-binding fragment in the preparation of a medicament for treating a tumor in a subject, wherein the medicament is for use in combination with a chemotherapeutic agent .
  • the chemotherapeutic drugs include, but are not limited to, platinum anti-tumor drugs, taxane anti-tumor drugs, antimetabolite anti-tumor drugs, camptothecin anti-tumor drugs, nitrogen mustard anti-tumor drugs, One or more of anthracycline anti-tumor drugs, vinblastine anti-tumor drugs, podophyllin alkaloid anti-tumor drugs, and hormonal anti-tumor drugs.
  • the chemotherapeutic drug is a platinum-based anti-tumor drug and/or an antimetabolite anti-tumor drug.
  • the chemotherapeutic drug is a platinum-based antitumor drug and/or a cytosine-based antitumor drug.
  • the chemotherapeutic drugs are cisplatin and gemcitabine.
  • the present disclosure provides use of an anti-TIM-3 antibody or antigen-binding fragment thereof in the preparation of a medicament for treating a tumor in a subject, wherein the medicament is used in conjunction with an anti-PD-1 antibody of the present disclosure. Antibody antigen-binding fragment, cisplatin, and gemcitabine were used in combination.
  • the present disclosure provides the use of an anti-TIM-3 antibody or antigen-binding fragment thereof and an anti-PD-1 antibody antigen-binding fragment in the preparation of a medicament for treating a tumor in a subject, wherein the medicament is For use in combination with cisplatin and gemcitabine.
  • in the method or use it includes administering to the subject an effective amount of a pharmaceutical combination of the present disclosure during a first treatment phase, and administering to the subject an effective amount of the present invention during a second treatment phase.
  • Disclosed drug combinations include administering to the subject an effective amount of a pharmaceutical combination of the present disclosure during a first treatment phase, and administering to the subject an effective amount of the present invention during a second treatment phase.
  • the method or use in the method or use, includes administering to the subject an effective amount of an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof in the first treatment phase.
  • an effective amount of an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof in the first treatment phase include administering to the subject an effective amount of an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof in the first treatment phase.
  • an effective amount of a drug combination including an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof is administered to the subject.
  • it in the method or use, includes administering to the subject an effective amount of an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof in the first treatment phase.
  • Drug combinations of fragments, platinum antineoplastic drugs, and antimetabolite antineoplastic drugs include:
  • an effective amount of a drug combination including an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof is administered to the subject.
  • it in the method or use, it includes administering to the subject an effective amount of an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof in the first treatment phase.
  • an effective amount of a drug combination including an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof is administered to the subject.
  • it in the method or use, it includes administering to the subject an effective amount of an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof in the first treatment phase.
  • an effective amount of a drug combination including an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof is administered to the subject.
  • the treatment cycles of the first treatment phase include 1-14 treatment cycles, preferably 2-12 treatment cycles, 2-10 treatment cycles, more preferably 2-8 treatment cycles, for example: 2 -8 treatment cycles, 3-8 treatment cycles, 4-8 treatment cycles, 2-7 treatment cycles, 3-7 treatment cycles, 4-7 treatment cycles, 2-6 treatment cycles, 3- 6 treatment cycles, or 4-6 treatment cycles; most preferably 4-6 treatment cycles, for example: 4 treatment cycles, 5 treatment cycles, and/or 6 treatment cycles.
  • the second treatment phase follows the first treatment phase. In some embodiments, the second treatment phase lasts from the end of the first treatment phase until clinical benefit is lost, toxicity is intolerable, the efficacy is evaluated as PD, and the researcher deems it unsuitable to continue medication.
  • the anti-TIM-3 antibody, or antigen-binding fragment thereof, and the anti-PD-1 antibody, or antigen-binding fragment thereof may be administered simultaneously, sequentially, and/or alternately. In some embodiments, in the method or use, the anti-TIM-3 antibody, or antigen-binding fragment thereof, and the anti-PD-1 antibody, or antigen-binding fragment thereof, are administered sequentially. In some embodiments, in the method or use, the anti-TIM-3 antibody, or antigen-binding fragment thereof, and the anti-PD-1 antibody, or antigen-binding fragment thereof, are administered simultaneously.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are each in the form of a pharmaceutical composition, which can be performed simultaneously, sequentially and /or alternate administration.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are each in the form of a pharmaceutical composition and are administered sequentially.
  • the anti-PD-1 antibody, or antigen-binding fragment thereof is administered first, followed by the anti-TIM-3 antibody, or antigen-binding fragment thereof.
  • the anti-TIM-3 antibody, or antigen-binding fragment thereof, and the anti-PD-1 antibody, or antigen-binding fragment thereof are each in the form of a pharmaceutical composition, and the anti-PD-1 antibody or antigen-binding fragment thereof is administered first.
  • -1 antibody or a pharmaceutical composition thereof or an antigen-binding fragment thereof and then administer a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof.
  • the anti-TIM-3 antibody, or antigen-binding fragment thereof, and the anti-PD-1 antibody, or antigen-binding fragment thereof are formulated in a single formulation and administered simultaneously.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and the chemotherapeutic agent may be administered simultaneously, sequentially, and/or alternately. Medication.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and the chemotherapeutic agent are each in the form of a pharmaceutical composition, which may Simultaneous, sequential and/or alternating administration.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, cisplatin, and gemcitabine may be administered simultaneously, sequentially, and/or Alternate administration.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, cisplatin, and gemcitabine are each in the form of a pharmaceutical composition, Can be administered simultaneously, sequentially and/or alternately.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are formulated in a single formulation, the single formulation and a chemotherapeutic agent , can be administered simultaneously, sequentially and/or alternately.
  • the anti-TIM-3 antibody, or antigen-binding fragment thereof, and the anti-PD-1 antibody, or antigen-binding fragment thereof are formulated in a single formulation, the single formulation, cisplatin and gemcitabine, which can be administered simultaneously, sequentially, and/or alternately.
  • the anti-TIM-3 antibody, or antigen-binding fragment thereof, and the anti-PD-1 antibody, or antigen-binding fragment thereof are formulated in a single formulation, and the single formulation and the chemotherapy-containing Pharmaceutical compositions of drugs can be administered simultaneously, sequentially and/or alternately.
  • the anti-TIM-3 antibody, or antigen-binding fragment thereof, and the anti-PD-1 antibody, or antigen-binding fragment thereof are formulated in a single formulation, the single formulation, containing cis
  • the platinum pharmaceutical composition and the pharmaceutical composition containing gemcitabine can be administered simultaneously, sequentially and/or alternately.
  • the anti-TIM-3 antibody, or antigen-binding fragment thereof, and the anti-PD-1 antibody, or antigen-binding fragment thereof are each administered in the same or different dosage regimens. In some embodiments, in the method or use, the anti-TIM-3 antibody, or antigen-binding fragment thereof, and the anti-PD-1 antibody, or antigen-binding fragment thereof, are each administered in different dosage regimens.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and the chemotherapeutic agent are each administered in the same or different dosage regimens. Medication. In some embodiments, in the method or use, the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, cisplatin, and gemcitabine are each in the same or different dosing regimens.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and cisplatin and gemcitabine are each administered in different Dosing according to the plan.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof is administered every week (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w) Administer once.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof is administered every 3 weeks.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof is administered once every 4 weeks.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof is administered at a dose of 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg each time.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof is administered at about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg each time , about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg, or a dosage within the range formed by any of the above values.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof is administered at a dose of about 1200 mg or about 1500 mg per administration.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks at 1200-1500 mg of the anti-TIM-3 antibody or antigen-binding fragment thereof. Dosage Administration of Antigen-Binding Fragments. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, at about 1200 mg or about 1500 mg of anti-TIM-3 antibody each time or antigen-binding fragments thereof.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof is administered once every 3 weeks at a dose of about 1200 mg or about 1500 mg of the anti-TIM-3 antibody or antigen-binding fragment thereof. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered once every 3 weeks at a dose of about 1200 mg of anti-TIM-3 antibody or antigen-binding fragment thereof.
  • the anti-PD-1 antibody or antigen-binding fragment thereof is administered every week (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w) Administer once.
  • the anti-PD-1 antibody or antigen-binding fragment thereof is administered every 2 weeks.
  • the anti-PD-1 antibody or antigen-binding fragment thereof is administered every 3 weeks.
  • the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 10-800 mg, 50-500 mg, or 100-200 mg each time.
  • the anti-PD-1 antibody or antigen-binding fragment thereof is administered at about 10 mg, about 50 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg each time , about 260 mg, about 280 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, or about 800 mg, or a dose in the range formed by any of the above values Apply.
  • the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of about 200 mg each time.
  • the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks at about 200 mg of the anti-PD-1 antibody or antigen thereof. Dosage administration of combined fragments. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered every 2 weeks at a dose of about 200 mg of anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered every 3 weeks at a dose of about 200 mg of anti-PD-1 antibody or antigen-binding fragment thereof.
  • the cisplatin in the method or use, is administered once every week (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w). In some embodiments, in the method or use, the cisplatin is administered every 3 weeks (q3w). In some embodiments, the cisplatin is administered at a dose of 40-80 mg/m 2 , or 40-75 mg/m 2 each time. In some embodiments, the cisplatin is administered at a dose of 40 mg/m 2 , 60 mg/m 2 , 75 mg/m 2 , 80 mg/m 2 , or a range of any of the above.
  • the cisplatin is administered once every 3 weeks at a dose of 40 mg/m 2 , 60 mg/m 2 , 75 mg/m 2 , or 80 mg/m 2 cisplatin. In some embodiments, the cisplatin is administered every 3 weeks at a dose of 75 mg/m cisplatin . In some embodiments, the cisplatin is administered every 3 weeks at a dose of 80 mg/m cisplatin .
  • the gemcitabine is administered once weekly. In some embodiments, the gemcitabine is administered at a dose of 0.5-1.0 g/m per time. In some embodiments, the gemcitabine is administered at a dose of 0.5 g/m 2 , 0.75 g/m 2 , or 1.0 g/m 2 each time. In some embodiments, the gemcitabine is administered at a dosage of 0.5-1.0 g/m 2 gemcitabine once a week for 2 weeks on and off for 1 week. In some embodiments, the gemcitabine is administered at a dosage of 0.5 g/m 2 , 0.75 g/m 2 or 1.0 g/m 2 gemcitabine once a week for 2 weeks on and off for 1 week. In some embodiments, the gemcitabine is administered at a dose of 1.0 g/m 2 gemcitabine once a week for 2 weeks on and off for 1 week.
  • the anti-TIM-3 antibody, or antigen-binding fragment thereof, and the anti-PD-1 antibody, or antigen-binding fragment thereof, respectively have the same or different treatment cycles.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof have the same treatment cycle, such as every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks for one treatment treatment cycle.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof have the same treatment cycle, for example, every 3 weeks is a treatment cycle.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and the chemotherapeutic agent each have the same or different treatment cycles.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, cisplatin, and gemcitabine each have the same or different treatment cycles.
  • anti-TIM-3 antibody or antigen-binding fragment thereof, anti-PD-1 antibody or antigen-binding fragment thereof, cisplatin and gemcitabine have the same treatment cycle, for example, every 1 week, every 2 weeks, every A treatment cycle is 3 weeks or every 4 weeks.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, cisplatin and gemcitabine have the same treatment cycle, for example, every 3 weeks is one treatment cycle.
  • a treatment cycle is every 3 weeks, and the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are administered in each treatment cycle.
  • every 3 weeks is a treatment cycle, and the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are administered separately in each treatment cycle.
  • a treatment cycle is every 3 weeks, and the anti-TIM-3 antibody or antigen-binding fragment thereof is administered on Day 1 of each treatment cycle, and on Day 1 of each treatment cycle.
  • Anti-PD-1 antibodies or antigen-binding fragments thereof are administered on the same day.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof is administered once every 3 weeks for a treatment cycle, on day 1 of each treatment cycle, and on day 1 of each treatment cycle.
  • Anti-PD-1 antibody or its antigen-binding fragment is administered once a day.
  • the anti-TIM-3 antibody, or antigen-binding fragment thereof, and the anti-PD-1 antibody, or antigen-binding fragment thereof are formulated in a single formulation.
  • treatment cycles are every 3 weeks, and the single formulation is administered during each treatment cycle.
  • the single formulation is administered once every 3 weeks in treatment cycles.
  • the single formulation is administered on Day 1 of each treatment cycle every 3 weeks.
  • the single formulation is administered once every 3 weeks in a treatment cycle on Day 1 of each treatment cycle.
  • about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof is administered every 3 weeks as a treatment cycle, and at each treatment cycle Approximately 200 mg of anti-PD-1 antibody or antigen-binding fragment thereof is administered during the treatment cycle. In some specific embodiments, in the methods or uses, about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof is administered on Day 1 of each 3-week treatment cycle. , approximately 200 mg of an anti-PD-1 antibody or antigen-binding fragment thereof is administered on Day 1 of each treatment cycle.
  • an anti-TIM-3 antibody or antigen-binding fragment thereof is administered on day 1 of each treatment cycle every 3 weeks, and on day 1 of each treatment cycle, Approximately 200 mg of anti-PD-1 antibody or antigen-binding fragment thereof is administered on day 1 of each treatment cycle.
  • every 3 weeks is a treatment cycle, and an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof, is administered in each treatment cycle. and chemotherapy drugs.
  • every 3 weeks is a treatment cycle, and an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof, is administered in each treatment cycle. Cisplatin and gemcitabine.
  • every 3 weeks is a treatment cycle, and anti-TIM-3 antibody or antigen-binding fragment thereof, anti-PD-1 antibody or antigen-binding fragment thereof, and anti-TIM-3 antibody or antigen-binding fragment thereof are administered respectively in each treatment cycle. Cisplatin was given once and gemcitabine was given twice.
  • a treatment cycle is every 3 weeks, and the anti-TIM-3 antibody or antigen-binding fragment thereof is administered on Day 1 of each treatment cycle, and on Day 1 of each treatment cycle.
  • Anti-PD-1 antibodies or antigen-binding fragments thereof were administered on day 1, cisplatin was administered on day 1 of each treatment cycle, and gemcitabine was administered on days 1 and 8 of each treatment cycle.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof is administered once every 3 weeks for a treatment cycle, on day 1 of each treatment cycle, and on day 1 of each treatment cycle.
  • the anti-PD-1 antibody or its antigen-binding fragment was administered once a day
  • cisplatin was administered once on the 1st day of each treatment cycle
  • gemcitabine was administered once on the 1st and 8th days of each treatment cycle.
  • the anti-TIM-3 antibody, or antigen-binding fragment thereof, and the anti-PD-1 antibody, or antigen-binding fragment thereof are formulated in a single formulation.
  • the single agent and the chemotherapeutic agent are administered in each treatment cycle every 3 weeks.
  • the single agent, cisplatin and gemcitabine are administered in treatment cycles every 3 weeks.
  • the single formulation is administered once every 3 weeks, cisplatin is administered once, and gemcitabine is administered twice in each treatment cycle.
  • treatment cycles are every 3 weeks, and the single dose is administered on Day 1 of each treatment cycle.
  • cisplatin was administered on day 1 of each treatment cycle and gemcitabine was administered on days 1 and 8 of each treatment cycle.
  • the single formulation is administered once every 3 weeks on Day 1 of each treatment cycle and cisplatin is administered once on Day 1 of each treatment cycle.
  • gemcitabine was administered once on days 1 and 8 of each treatment cycle.
  • about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof is administered every 3 weeks as a treatment cycle, and at each treatment cycle Approximately 200 mg of anti-PD-1 antibody or antigen-binding fragment thereof is administered in each treatment cycle, 75 mg/ m of cisplatin is administered in each treatment cycle, and 2.0 g/m of gemcitabine is administered in each treatment cycle. In some specific embodiments, in the methods or uses, about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof is administered on Day 1 of each 3-week treatment cycle.
  • about 1200 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof is administered on day 1 of each treatment cycle every 3 weeks, and on day 1 of each treatment cycle, Approximately 200 mg of anti-PD-1 antibody or antigen-binding fragment thereof is administered on day 1 of each treatment cycle, 75 mg/ m2 of cisplatin is administered on day 1 of each treatment cycle, and cisplatin is administered on days 1 and 8 of each treatment cycle.
  • Gemcitabine at 1.0g/ m2 was given on each day.
  • chemotherapeutic agent is a platinum-based anti-tumor drug and/or an antimetabolite anti-tumor drug.
  • the chemotherapeutic drug is a platinum-based antitumor drug and/or a cytosine-based antitumor drug. In some specific embodiments, the chemotherapeutic drugs are cisplatin and gemcitabine.
  • each treatment cycle in each treatment cycle, (0.1-180):1, (0.2-50):1, (0.5-9):1, (3-7.5):1, (4-7.5 ):1 or (6-7.5):1 mass ratio of anti-TIM-3 antibody or antigen-binding fragment thereof: anti-PD-1 antibody or antigen-binding fragment thereof, administering anti-TIM-3 antibody or antigen-binding fragment thereof to the subject binding fragment and an anti-PD-1 antibody or antigen-binding fragment thereof; optionally, the subject is further administered cisplatin and gemcitabine.
  • the anti-TIM-3 antibody, or antigen-binding fragment thereof, and the anti-PD-1 antibody, or antigen-binding fragment thereof are administered in multiple doses or in a single dose during each treatment cycle. In some embodiments, the anti-TIM-3 antibody, or antigen-binding fragment thereof, and the anti-PD-1 antibody, or antigen-binding fragment thereof, are administered in multiple doses during each treatment cycle. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and the chemotherapeutic agent are administered in multiple doses or in a single dose during each treatment cycle.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, cisplatin, and gemcitabine are administered in multiple doses or in a single dose during each treatment cycle. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, cisplatin, and gemcitabine are administered in multiple doses during each treatment cycle.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof can be selected from 0.01 to 50 mg/kg, 0.1 to 40 mg/kg, 0.1 to 35 mg/kg, 0.1 to 30 mg /kg, 0.1 to 25mg/kg, 0.1 to 20mg/kg, 0.1 to 15mg/kg, 0.1 to 10mg/kg, 1 to 40mg/kg, 1 to 35mg/kg, 1 to 30mg/kg, 1 to 25mg/kg , 1 to 20mg/kg, 1 to 15mg/kg, 1 to 10mg/kg, 1 to 3mg/kg, 3 to 40mg/kg, 3 to 35mg/kg, 3 to 30mg/kg, 3 to 25mg/kg, 3 to 20 mg/kg, 3 to 15 mg/kg, 3 to 10 mg/kg, 10 to 40 mg/kg, 10 to 30 mg/kg, 10 to 25 mg/kg, or 20 to 25 mg/kg; or 1-2400mg, 20-1800
  • the anti-PD-1 antibody or antigen-binding fragment thereof can be selected from 0.01 to 50 mg/kg, 0.1 to 40 mg/kg, 0.1 to 35 mg/kg, 0.1 to 30 mg /kg, 0.1 to 25mg/kg, 0.1 to 20mg/kg, 0.1 to 15mg/kg, 0.1 to 10mg/kg, 1 to 30mg/kg, 1 to 25mg/kg, 1 to 20mg/kg, 1 to 15mg/kg , 1 to 10mg/kg, 1 to 8mg/kg, 1 to 5mg/kg, 1 to 3mg/kg, 3 to 30mg/kg, 3 to 25mg/kg, 3 to 20mg/kg, 3 to 15mg/kg, 3 to 10 mg/kg, 3 to 8 mg/kg, or 3 to 5 mg/kg; or 1-1000 mg, 10-1000 mg, 10-800 mg, 20-800 mg, 40-800 mg, 50-700 mg, or A uniform dose of 200 mg was administered to 0.01 to 50 mg/kg, 0.1
  • the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, a chemotherapeutic agent e.g., cisplatin or gemcitabine
  • Drug regimens e.g., dosing cycles, dosing doses, and dosage adjustments
  • a treatment cycle of anti-TIM-3 antibody or antigen-binding fragment thereof and/or anti-PD-1 antibody or antigen-binding fragment thereof can be adjusted to 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, or 9 weeks.
  • a single dose of cisplatin may be 40-80 mg/m 2 , or 40-75 mg/m 2 .
  • a single dose of cisplatin can be 40 mg/m 2 , 60 mg/m 2 , 75 mg/m 2 or 80 mg/m 2 .
  • a single dose of cisplatin can be 50-200 mg.
  • cisplatin can be administered at a dose of 40-80 mg/ m2 , or 40-75 mg/ m2 in a single treatment cycle.
  • cisplatin can be administered at a dose of 40 mg/m 2 , 60 mg/m 2 , 75 mg/m 2 , or 80 mg/m 2 in a single treatment cycle. In some embodiments, cisplatin can be administered at a dose of 50-200 mg in a single treatment cycle.
  • a single dose of gemcitabine may be 0.5-1.0 g/m 2 .
  • a single dose of gemcitabine may be 0.5 g/m 2 , 0.75 g/m 2 , or 1.0 g/m 2 .
  • a single dose of gemcitabine can be 0.5-2.5 g.
  • gemcitabine may be administered at a dose of 1.0-2.0 g/ m2 in a single treatment cycle.
  • gemcitabine may be administered at a dose of 1.0 g/m 2 , 1.25 g/m 2 , 1.5 g/m 2 , 1.75 g/m 2 , or 2.0 g/m 2 in a single treatment cycle. In some embodiments, gemcitabine may be administered at a dose of 1.0-5.0 g in a single treatment cycle.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof of the present disclosure includes: the heavy chain CDR1 (HCDR1) of the amino acid sequence shown in SEQ ID NO: 1 or 21, the heavy chain CDR1 (HCDR1) of the amino acid sequence shown in SEQ ID NO: 2 or 22 HCDR2 whose amino acid sequence is shown, HCDR3 whose amino acid sequence is shown in SEQ ID NO:3 or 23, light chain CDR1 (LCDR1) whose amino acid sequence is shown in SEQ ID NO:4 or 24, and amino acid sequence shown in SEQ ID NO:5 or 25 LCDR2, and LCDR3 of the amino acid sequence shown in SEQ ID NO: 6 or 26.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof of the present disclosure includes: HCDR1 of the amino acid sequence shown in SEQ ID NO: 1, HCDR2 of the amino acid sequence shown in SEQ ID NO: 2, SEQ ID NO : HCDR3 with the amino acid sequence shown in SEQ ID NO: 3, LCDR1 with the amino acid sequence shown in SEQ ID NO: 4, LCDR2 with the amino acid sequence shown in SEQ ID NO: 5, and LCDR3 with the amino acid sequence shown in SEQ ID NO: 6.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof of the present disclosure includes: HCDR1 of the amino acid sequence shown in SEQ ID NO:21, HCDR2 of the amino acid sequence shown in SEQ ID NO:22, SEQ ID NO : HCDR3 with the amino acid sequence shown in SEQ ID NO:23, LCDR1 with the amino acid sequence shown in SEQ ID NO:24, LCDR2 with the amino acid sequence shown in SEQ ID NO:25, and LCDR3 with the amino acid sequence shown in SEQ ID NO:26.
  • the CDR sequences of anti-TIM-3 antibodies or antigen-binding fragments thereof are shown in Table 1.
  • CDR complementarity determining region
  • anti-TIM-3 antibodies or antigen-binding fragments thereof comprising the following amino acid sequences are also encompassed within the scope of the anti-TIM-3 antibodies or antigen-binding fragments thereof of the present disclosure: HCDR1 of the amino acid sequence shown in SEQ ID NO: 1, HCDR2 with the amino acid sequence shown in SEQ ID NO:2, HCDR3 with the amino acid sequence shown in ARRYYGYDAMDY (SEQ ID NO:31), LCDR1 with the amino acid sequence shown in SEQ ID NO:4, LCDR2 with the amino acid sequence shown in SEQ ID NO:5 , and LCDR3 of the amino acid sequence shown in SEQ ID NO:6.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, or identical to the amino acid sequence set forth in SEQ ID NO: 7 or 27. 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical
  • the heavy chain variable region, and the amino acid sequence has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, A light chain variable region that is 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region of the amino acid sequence set forth in SEQ ID NO:7, and a light chain variable region of the amino acid sequence set forth in SEQ ID NO:8 district.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region of the amino acid sequence set forth in SEQ ID NO: 27, and a light chain variable region of the amino acid sequence set forth in SEQ ID NO: 28 district.
  • the amino acid sequence of the heavy chain variable region of the anti-TIM-3 antibody or antigen-binding fragment thereof is set forth in SEQ ID NO: 7, and the amino acid sequence of the light chain variable region is set forth in SEQ ID NO.
  • amino acid sequence of the heavy chain variable region of the anti-TIM-3 antibody or antigen-binding fragment thereof is set forth in SEQ ID NO: 27, and the amino acid sequence of the light chain variable region is set forth in SEQ ID NO. Shown in NO:28.
  • an anti-TIM-3 antibody or antigen-binding fragment thereof of the present disclosure includes a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region includes HCDR1, HCDR2, and HCDR3, and the light chain may
  • the variable region includes LCDR1, LCDR2 and LCDR3, wherein HCDR1 includes the amino acid sequence shown in SEQ ID NO:1, HCDR2 includes the amino acid sequence shown in SEQ ID NO:2, HCDR3 includes the amino acid sequence shown in SEQ ID NO:3, and LCDR1 includes SEQ
  • the light chain variable region comprises at least 80%, 81%, 82%, 83%, 84%, 85% with SEQ ID NO:8 , 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical amino acid sequences .
  • the anti-TIM-3 antibody or antigen-binding fragment thereof may further comprise an immunoglobulin constant region, or a fragment, analog, variant or derivative of the constant region.
  • the constant region comprises a heavy chain constant region and a light chain constant region.
  • the heavy chain constant region is derived from a human immunoglobulin heavy chain, such as IgG1, IgG2, IgG3 and IgG4, or a heavy chain of another class of immunoglobulin, preferably an IgG4 heavy chain.
  • the light chain constant region is from a human immunoglobulin light chain, such as a kappa light chain or a lambda light chain of a human immunoglobulin.
  • the constant region may comprise any modification described herein, such as insertion, deletion, substitution, or chemical modification of amino acids.
  • the constant region contains mutations that alter effector function.
  • any amino acid residue of the constant region may be substituted with an amino acid residue of any allotype.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, or identical to the amino acid sequence set forth in SEQ ID NO: 9 or 29. 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical
  • the heavy chain, and the amino acid sequence has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, A light chain that is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a heavy chain of the amino acid sequence set forth in SEQ ID NO:9, and a light chain of the amino acid sequence set forth in SEQ ID NO:10. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a heavy chain of the amino acid sequence set forth in SEQ ID NO:29, and a light chain of the amino acid sequence set forth in SEQ ID NO:30. In some specific embodiments, the amino acid sequence of the heavy chain of the anti-TIM-3 antibody or antigen-binding fragment thereof is set forth in SEQ ID NO:9, and the amino acid sequence of the light chain is set forth in SEQ ID NO:10. In some specific embodiments, the amino acid sequence of the heavy chain of the anti-TIM-3 antibody or antigen-binding fragment thereof is set forth in SEQ ID NO:29, and the amino acid sequence of the light chain is set forth in SEQ ID NO:30.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof of the present disclosure is mAb 50B5 or antigen-binding fragment thereof described in the patent application document with publication number WO2020041520 or CN112566936A, or a chimeric antibody of mAb 50B5 or its antigen-binding fragment.
  • Antigen-binding fragments, or humanized antibodies of mAb 50B5 or antigen-binding fragments thereof are examples of antibodies 50B5 or antigen-binding fragment thereof.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof of the present disclosure is mAb 15B4 or its antigen-binding fragment described in the patent application document with publication number WO2020041520 or CN112566936A, or a chimeric antibody of mAb 15B4 or An antigen-binding fragment thereof, or a humanized antibody of mAb 15B4, or an antigen-binding fragment thereof.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof of the present disclosure is selected from the group consisting of Sabatolimab, Cobolimab, Surzebiclimab, Lomvastomig, Hengrui Medicine’s SHR-1702, Agenus’ INCAGN-2390, WuXi Biologics’ BC- 3402, Verizhibo’s LBL-003, Jianxin Biotech’s LNL-005, or BMS’s BMS-986258.
  • the anti-PD-1 antibody or antigen-binding fragment thereof of the present disclosure includes: HCDR1 of the amino acid sequence shown in SEQ ID NO: 11, HCDR2 of the amino acid sequence shown in SEQ ID NO: 12, SEQ ID NO : HCDR3 with the amino acid sequence shown in SEQ ID NO: 13, LCDR1 with the amino acid sequence shown in SEQ ID NO: 14, LCDR2 with the amino acid sequence shown in SEQ ID NO: 15, and LCDR3 with the amino acid sequence shown in SEQ ID NO: 16.
  • the CDR sequences of anti-PD-1 antibodies or antigen-binding fragments thereof are shown in Table 2.
  • CDR complementarity determining region
  • a given antibody or region thereof e.g., variable region
  • CDR regions have been shown in Table 2, when it comes to defining an antibody with specific CDR sequences, the scope of the antibody encompasses any numbering system definition (e.g., AbM, Kabat, CCG, Chothia, IMGT, or One or a combination of several of the definitions of Contact, etc.) CDR sequence limitation of antibodies.
  • the anti-PD-1 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85% identical to the amino acid sequence set forth in SEQ ID NO: 17 , 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity of the heavy chain
  • the variable region, and the amino acid sequence has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90% of the amino acid sequence shown in SEQ ID NO:18 %, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity of the light chain variable region.
  • the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region of the amino acid sequence set forth in SEQ ID NO: 17, and a light chain variable region of the amino acid sequence set forth in SEQ ID NO: 18 district.
  • the amino acid sequence of the heavy chain variable region of the anti-PD-1 antibody or antigen-binding fragment thereof is as shown in SEQ ID NO: 17, and the amino acid sequence of the light chain variable region is as shown in SEQ ID NO. Shown in NO:18.
  • the anti-PD-1 antibodies or antigen-binding fragments thereof of the present disclosure comprise a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3, and the light chain may
  • the variable region includes LCDR1, LCDR2 and LCDR3, wherein HCDR1 includes the amino acid sequence shown in SEQ ID NO:11, HCDR2 includes the amino acid sequence shown in SEQ ID NO:12, HCDR3 includes the amino acid sequence shown in SEQ ID NO:13, and LCDR1 includes SEQ
  • the light chain variable region comprises at least 80%, 81%, 82%, 83%, 84%, 85% with SEQ ID NO: 18 , 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical amino acid sequences .
  • the anti-PD-1 antibody or antigen-binding fragment thereof may further comprise a constant region of an immunoglobulin, or a fragment, analog, variant or derivative of the constant region.
  • the constant region comprises a heavy chain constant region and a light chain constant region.
  • the heavy chain constant region is from a human immunoglobulin heavy chain, such as IgG1, IgG2, IgG3 and IgG4 or a heavy chain of another class of immunoglobulin, preferably an IgG1 heavy chain.
  • the light chain constant region is from a human immunoglobulin light chain, such as a kappa light chain or a lambda light chain of a human immunoglobulin.
  • the constant region may comprise any modification described herein, such as insertion, deletion, substitution, or chemical modification of amino acids.
  • the constant region contains mutations that alter effector function.
  • any amino acid residue of the constant region may be substituted with an amino acid residue of any allotype.
  • the anti-PD-1 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85% identical to the amino acid sequence set forth in SEQ ID NO: 19 , 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity of the heavy chain , and the amino acid sequence has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91% with the amino acid sequence shown in SEQ ID NO:20 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity of the light chain.
  • the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain of the amino acid sequence set forth in SEQ ID NO: 19, and a light chain of the amino acid sequence set forth in SEQ ID NO: 20.
  • the heavy chain amino acid sequence of the anti-PD-1 antibody or antigen-binding fragment thereof is set forth in SEQ ID NO: 19, and the light chain amino acid sequence is set forth in SEQ ID NO: 20.
  • the anti-PD-1 antibody or antigen-binding fragment thereof of the present disclosure is selected from the group consisting of Nivolumab, Pembrolizumab, Toripalimab, Sintilimab, Camrelizumab, Tislelizumab, Zimberelimab, Balstilimab, Genoumab Anti-(geptanolimab), Livzon Pharmaceutical LZM009, Cemiplimab, Serplulimab, Prolgolimab, Pucotenlimab (code HX008), Nofazinlimab, Finotonlimab, Dostarlimab, Cetrelimab , Qilu Pharmaceutical QL1604, Spartalizumab, Retifanlimab, Sasanlimab, Rulonilimab (code name F520), or Shangjian Biotechnology SG001.
  • compositions containing antibodies or antigen-binding fragments thereof are provided.
  • the unit dose of the pharmaceutical composition containing an anti-TIM-3 antibody or antigen-binding fragment thereof is 60-1800 mg, 100-1600 mg, 120-1600 mg, 180-1200 mg, or 240-600 mg of anti-TIM -3 antibody or antigen-binding fragment thereof, for example, about 60 mg, about 120 mg, about 160 mg, about 180 mg, about 200 mg, about 240 mg, about 280 mg, about 300 mg, about 320 mg, about 360 mg, about 400 mg, about 420 mg, about 440 mg, about 480mg, about 520mg, about 540mg, about 560mg, about 600mg, about 640mg, about 660mg, about 680mg, about 720mg, about 760mg, about 780mg, about 800mg, about 840mg, about 880mg, about 900mg, about 920mg, about 960mg, About 1000mg, about 1020mg, about 1040mg, about 1080mg, about
  • the unit dose of the pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof is 10-500 mg, 50-500 mg, 50-200 mg, or 100-200 mg of an anti-TIM-3 antibody or The antigen-binding fragment thereof, for example, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg , about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg,
  • the pharmaceutical composition containing an anti-TIM-3 antibody or antigen-binding fragment thereof may further include one or more pharmaceutically acceptable excipients to form a suitable formulation.
  • the pharmaceutical composition containing an anti-PD-1 antibody or antigen-binding fragment thereof may further include one or more pharmaceutically acceptable excipients to form a suitable formulation.
  • the preparations include, but are not limited to, tablets, lozenges, pills, capsules (e.g., hard capsules, soft capsules, enteric capsules, microcapsules), elixirs, granules, syrups, injections (i.e., suitable for injection) formulations, such as those suitable for intramuscular, intravenous, intraperitoneal, subcutaneous injection), granules, emulsions, suspensions, solutions, dispersions and sustained-release formulations for oral or parenteral administration.
  • injections i.e., suitable for injection formulations, such as those suitable for intramuscular, intravenous, intraperitoneal, subcutaneous injection
  • granules, emulsions, suspensions, solutions, dispersions and sustained-release formulations for oral or parenteral administration i.e., suitable for injection
  • the anti-TIM-3 antibody, or antigen-binding fragment thereof, and/or the anti-PD-1 antibody, or antigen-binding fragment thereof is formulated for parenteral administration.
  • anti-TIM-3 antibodies, or antigen-binding fragments thereof, and/or anti-PD-1 antibodies, or antigen-binding fragments thereof are formulated for administration by intravenous, intramuscular, subcutaneous, or other parenteral routes. preparation.
  • the anti-TIM-3 antibody, or antigen-binding fragment thereof, and/or the anti-PD-1 antibody, or antigen-binding fragment thereof is formulated for intravenous, intramuscular, or subcutaneous administration.
  • anti-TIM-3 antibodies or antigen-binding fragments thereof and/or anti-PD-1 antibodies or antigen-binding fragments thereof may be formulated as injectables.
  • the anti-TIM-3 antibody, or antigen-binding fragment thereof, and/or the anti-PD-1 antibody, or antigen-binding fragment thereof is formulated for intravenous injection or infusion.
  • the anti-TIM-3 antibody, or antigen-binding fragment thereof, and the anti-PD-1 antibody, or antigen-binding fragment thereof are formulated in a single formulation.
  • anti-TIM-3 antibodies or antigen-binding fragments thereof, anti-PD-1 antibodies or antigen-binding fragments thereof are formulated with one or more pharmaceutically acceptable excipients to form a suitable medicament combination.
  • the anti-TIM-3 antibody, or antigen-binding fragment thereof, and the anti-PD-1 antibody, or antigen-binding fragment thereof are formulated separately (i.e., each is in the form of a pharmaceutical composition).
  • an anti-TIM-3 antibody, or antigen-binding fragment thereof is combined with one or more pharmaceutically acceptable Acceptable excipients are formulated together to form suitable pharmaceutical compositions.
  • an anti-PD-1 antibody or antigen-binding fragment thereof is formulated with one or more pharmaceutically acceptable excipients to form a suitable pharmaceutical composition.
  • excipient is used to describe any ingredient other than a compound of the present disclosure. The choice of excipient will depend largely on factors such as the particular mode of administration, the excipient's effect on solubility and stability, and the nature of the dosage form.
  • pharmaceutically acceptable excipients include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. Some examples of pharmaceutically acceptable excipients are water, saline, dextrose, glycerol, ethanol, etc., and combinations thereof. In many cases, isotonic agents are included in pharmaceutical compositions. Other examples of pharmaceutically acceptable excipients are wetting agents or minor amounts of auxiliary substances, such as wetting or emulsifying agents, preservatives or buffers, which increase the storage life or effectiveness of the antibody.
  • the pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof is a water-soluble injection solution.
  • the pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof is a water-soluble injection solution.
  • the pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof is a water-soluble injection.
  • the water-soluble injection includes, but is not limited to, water-soluble preparations that have not been lyophilized or water-soluble preparations reconstituted with lyophilized powder.
  • the pharmaceutical composition containing an anti-TIM-3 antibody or antigen-binding fragment thereof is a lyophilized preparation.
  • the pharmaceutical composition containing an anti-PD-1 antibody or antigen-binding fragment thereof is a lyophilized preparation.
  • the pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof is a lyophilized preparation.
  • the freeze-dried preparation refers to a preparation prepared from an aqueous solution undergoing a freeze-drying process, in which the substance is first frozen, and then the amount of solvent is reduced by sublimation (primary drying process), and then the amount of solvent is reduced by desorption (secondary drying). process) until the amount of solvent is such that it no longer supports biological activity or chemical reaction. Lyophilized formulations of the present disclosure may also be dried by other methods known in the art, such as spray drying and bubble drying.
  • the concentration of anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical composition containing anti-PD-1 antibody or antigen-binding fragment thereof is 0.1-50 mg/mL, 0.5-30 mg/mL, 0.8 -20 mg/mL, 1-15 mg/mL, 1-10 mg/mL, 1-5 mg/mL, 2-20 mg/mL, 2-15 mg/mL, 2-10 mg/mL, or 2-5 mg/mL. In some specific embodiments, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is about 0.8 mg/mL, about 1 mg/mL, about 2 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5 mg/mL.
  • the concentration of anti-PD-1 antibody or antigen-binding fragment thereof is about 1 mg/mL. In some embodiments, the concentration of anti-PD-1 antibody or antigen-binding fragment thereof is about 2 mg/mL. In some embodiments, the concentration of anti-PD-1 antibody or antigen-binding fragment thereof is about 5 mg/mL. In some embodiments, the concentration of anti-PD-1 antibody or antigen-binding fragment thereof is about 10 mg/mL.
  • the anti-PD-1 antibody or antigen-binding fragment thereof is in the form of a pharmaceutical composition comprising an anti-PD-1 antibody or antigen-binding fragment thereof, a buffer, an isotonicity regulator/stabilizer, and a surface active agent.
  • the anti-PD-1 antibody or antigen-binding fragment thereof is in the form of a liquid pharmaceutical composition (such as an injection), which includes an anti-PD-1 antibody or antigen-binding fragment thereof, sodium acetate trihydrate, ice Acetic acid, sorbitol and polysorbate 80.
  • the chemotherapeutic drugs include, but are not limited to, platinum anti-tumor drugs (including, but not limited to, oxaliplatin, cisplatin, carboplatin, nedaplatin, bicycloplatin, imiplatin, loplatin, Picoplatin, Lobaplatin, triplatin tetranitrate, phenanthroplatin, satraplatin), camptothecin anti-tumor drugs (including but not limited to camptothecin, hydroxycamptothecin, aminocamptothecin, Irinotecan, topotecan, irinotecan, rubitecan, lurotecan (lurtotecan), gemotecan, karenitecin, 7-ethylcamptothecin), taxane antineoplastic drugs (including but not limited to paclitaxel, paclitaxel liposomes, albumin-bound paclitaxel and docetaxel), nitrogen mustard anti-tumor drugs (including but
  • the chemotherapeutic drug is selected from one or more of platinum-based antitumor drugs, taxane-based antitumor drugs, and antimetabolite anti-tumor drugs. In some embodiments, the chemotherapeutic drug is a platinum-based anti-tumor drug and/or an antimetabolite anti-tumor drug. In some embodiments, the chemotherapeutic drug is a platinum-based antitumor drug and/or a cytosine-based antitumor drug.
  • the platinum anti-tumor drug is selected from the group consisting of cisplatin, carboplatin, nedaplatin, bicycloplatin, picoplatin, oxaliplatin, imiplatin, loplatin, loplatin, triplatinum tetranitrate, phenanthroplatin or
  • satraplatin are preferably carboplatin and/or cisplatin, and more preferably cisplatin.
  • the antimetabolite anti-tumor drug is selected from one or more of cytarabine, gemcitabine, azacitidine or amcitabine, preferably gemcitabine.
  • the cytosine anti-tumor drug is selected from one or more of cytarabine, gemcitabine, azacitidine or amcitabine, preferably gemcitabine.
  • the chemotherapeutic drugs are platinum anti-tumor drugs and antimetabolite anti-tumor drugs. In some embodiments, the chemotherapeutic drugs are platinum-based antitumor drugs and cytosine-based antitumor drugs. In some specific embodiments, the chemotherapeutic drugs are cisplatin and gemcitabine.
  • the chemotherapeutic drug is administered according to a known dosage regimen (including dosage cycle, dosage and dosage adjustment, and route of administration).
  • gemcitabine As used in this disclosure, the chemical name of gemcitabine is 2'-deoxy-2',2'-difluorocytidine ( ⁇ -isomer), which has the structural formula of Formula (I):
  • gemcitabine includes its free base form and also includes pharmaceutically acceptable salts, and the non-salt forms or salts are included in the protection scope of the present disclosure.
  • Gemcitabine may be administered in its free base form or in the form of its pharmaceutically acceptable salt.
  • pharmaceutically acceptable salts of gemcitabine are within the scope of the present disclosure, and the salts can be produced from different organic acids and inorganic acids according to methods well known in the art.
  • the inorganic acid can be selected from hydrochloric acid, hydrobromic acid, sulfuric acid, Nitric acid or phosphoric acid
  • the organic acid can be selected from succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid or methanesulfonic acid.
  • the pharmaceutically acceptable salt of gemcitabine may be the hydrochloride salt of gemcitabine.
  • gemcitabine is administered as its hydrochloride salt. In some embodiments, gemcitabine is administered as its monohydrochloride salt.
  • the unit dose of the cisplatin-containing pharmaceutical composition is 2.5 mg, 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 50 mg and/or 100 mg of cisplatin. In some embodiments, the unit dose of the cisplatin-containing pharmaceutical composition is 20 mg, 30 mg, and/or 100 mg of cisplatin. In some embodiments, the unit dose of the cisplatin-containing pharmaceutical composition is 30 mg of cisplatin.
  • the unit dose of the gemcitabine-containing pharmaceutical composition is 0.2 mg or 1.0 mg of gemcitabine.
  • the cisplatin-containing pharmaceutical composition is a formulation suitable for injection. In some embodiments, the cisplatin-containing pharmaceutical composition is a liquid formulation. In some embodiments, the cisplatin-containing pharmaceutical composition is a liquid formulation suitable for injection. In some embodiments, the cisplatin-containing pharmaceutical composition is a liquid formulation suitable for intravenous injection. In some embodiments, the cisplatin-containing pharmaceutical composition is a lyophilized formulation. In some embodiments, the cisplatin-containing pharmaceutical composition is a powder.
  • the gemcitabine-containing pharmaceutical composition is a formulation suitable for injection.
  • the The pharmaceutical composition of citabine is a liquid preparation.
  • the gemcitabine-containing pharmaceutical composition is a liquid formulation suitable for injection.
  • the gemcitabine-containing pharmaceutical composition is a liquid formulation suitable for intravenous injection.
  • the gemcitabine-containing pharmaceutical composition is a lyophilized formulation.
  • the gemcitabine-containing pharmaceutical composition is a powder.
  • liquid preparations suitable for injection can be prepared by conventional methods using pharmaceutically acceptable carriers well known in the art.
  • Pharmaceutically acceptable carriers include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, etc.
  • pharmaceutically acceptable carriers for the cisplatin-containing liquid formulation suitable for injection include polyethylene glycol 400 and sodium chloride.
  • pharmaceutically acceptable carriers for the liquid formulation of gemcitabine-containing suitable for injection include mannitol, sodium acetate, hydrochloric acid, and sodium hydroxide.
  • Each component of the pharmaceutical combination of the present disclosure may be administered independently, or part or all thereof may be administered together by any suitable route, including, but not limited to, oral or parenteral routes (e.g., via intravenous, intramuscular , topical or subcutaneous route) administration.
  • each component of the pharmaceutical combination of the present disclosure may be administered individually, or part or all thereof may be administered together orally or by injection, such as by intravenous or subcutaneous injection.
  • the components in the pharmaceutical combination of the present disclosure may be formulated independently, or part or all of them may be formulated together into suitable dosage forms, including but not limited to tablets, lozenges, pills, capsules (e.g., hard capsules, soft capsules, Enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal, subcutaneous), granules, powders, emulsions, suspensions, solutions, dispersions and for oral administration or sustained-release formulations for parenteral administration.
  • each component of the pharmaceutical combination of the present disclosure may be administered independently, or some or all of them may be co-formulated into an injection.
  • the components in the pharmaceutical combination of the present disclosure may be each independently, or some or all of them may together contain pharmaceutically acceptable carriers and/or excipients.
  • compositions of the present disclosure may also include additional therapeutic agents.
  • the additional therapeutic agent may be a tumor therapeutic agent known in the art.
  • a tumor of the present disclosure is a malignant tumor (i.e., a cancer); by malignant tumor is any malignant and/or invasive growth caused by abnormal cell growth.
  • the tumor is a solid tumor.
  • the tumor is a treatment-na ⁇ ve, refractory, recurrent, metastatic, and/or advanced solid tumor.
  • the tumor is a recurrent and/or metastatic solid tumor.
  • the tumor is nasopharyngeal carcinoma. In some embodiments, the tumor is treatment-na ⁇ ve, refractory, recurrent, metastatic and/or advanced nasopharyngeal carcinoma. In some embodiments, the tumor is treatment-na ⁇ ve nasopharyngeal carcinoma. In some embodiments, the tumor is advanced nasopharyngeal carcinoma. In some embodiments, the tumor is advanced, treatment-na ⁇ ve nasopharyngeal carcinoma. In some embodiments, the tumor is recurrent nasopharyngeal carcinoma. In some embodiments, the tumor is metastatic nasopharyngeal carcinoma. In some embodiments, the tumor is recurrent and/or metastatic nasopharyngeal carcinoma.
  • the nasopharyngeal carcinoma is differentiated or undifferentiated nasopharyngeal carcinoma.
  • the nasopharyngeal carcinoma is keratinizing or non-keratinizing nasopharyngeal carcinoma.
  • the nasopharyngeal carcinoma is undifferentiated non-keratinizing nasopharyngeal carcinoma.
  • the nasopharyngeal carcinoma is undifferentiated non-keratinizing advanced nasopharyngeal carcinoma.
  • the nasopharyngeal carcinoma is undifferentiated nonkeratinizing recurrent and/or metastatic nasopharyngeal carcinoma.
  • the nasopharyngeal cancer is stage IV nasopharyngeal cancer. In some embodiments, the nasopharyngeal cancer is stage IVb nasopharyngeal cancer. In some embodiments, the nasopharyngeal cancer is a nasopharyngeal cancer that is not amenable to local treatment. In some embodiments, the nasopharyngeal cancer is stage IVb or recurrent nasopharyngeal cancer not suitable for local treatment.
  • the subject with nasopharyngeal cancer has not previously been treated for nasopharyngeal cancer (eg, lacks an effective treatment regimen). In some embodiments, the subject with nasopharyngeal cancer has not previously received systemic therapy to treat nasopharyngeal cancer (eg, has not previously received systemic therapy to treat advanced, untreated nasopharyngeal cancer). In some embodiments, the subject with nasopharyngeal cancer has not previously received radiation therapy, chemotherapy, and/or immunotherapy to treat nasopharyngeal cancer.
  • the nasopharyngeal cancer is late-stage, untreated nasopharyngeal cancer, and the subject with late-stage, untreated nasopharyngeal cancer has not previously received systemic therapy to treat nasopharyngeal cancer.
  • the nasopharyngeal cancer is late-stage, untreated nasopharyngeal cancer, and the subject with late-stage, untreated nasopharyngeal cancer has not previously received radiotherapy, chemotherapy, and/or immunotherapy for the treatment of nasopharyngeal cancer.
  • the nasopharyngeal carcinoma is an advanced stage and initially treated nasopharyngeal carcinoma.
  • Pharyngeal cancer the subject with advanced treatment-naive nasopharyngeal cancer has not previously received an immune checkpoint (eg, PD-1 or PD-L1) inhibitor for the treatment of nasopharyngeal cancer.
  • an immune checkpoint eg, PD-1 or PD-L1
  • the nasopharyngeal cancer is late-stage, treatment-na ⁇ ve nasopharyngeal cancer, and the subject of the late-stage, untreated nasopharyngeal cancer has not previously received systemic therapy and immune checkpoints (e.g., PD-1 or PD-L1 ) inhibitors for the treatment of nasopharyngeal carcinoma.
  • the nasopharyngeal cancer is recurrent and/or metastatic nasopharyngeal cancer in a subject who has not previously received systemic therapy for the treatment of nasopharyngeal cancer. In some embodiments, the nasopharyngeal cancer is recurrent and/or metastatic nasopharyngeal cancer in a subject who has not previously received radiotherapy, chemotherapy, and/or immunotherapy. Treatment of nasopharyngeal cancer.
  • the nasopharyngeal cancer is recurrent and/or metastatic nasopharyngeal cancer in a subject who has not previously received an immune checkpoint (e.g., PD-1 or PD -L1) inhibitor for the treatment of nasopharyngeal carcinoma.
  • an immune checkpoint e.g., PD-1 or PD -L1
  • the nasopharyngeal cancer is recurrent and/or metastatic nasopharyngeal cancer in a subject who has not previously received systemic therapy and immune checkpoints (e.g., PD -1 or PD-L1) inhibitors for the treatment of nasopharyngeal carcinoma.
  • the subject with nasopharyngeal cancer has not previously received systemic therapy to treat nasopharyngeal cancer.
  • the subject with recurrent and/or metastatic nasopharyngeal carcinoma has not previously received systemic therapy to treat recurrent and/or metastatic nasopharyngeal carcinoma.
  • the subject with advanced nasopharyngeal cancer has not previously received systemic therapy for the treatment of advanced nasopharyngeal cancer.
  • the subject with nasopharyngeal carcinoma has not previously received immune checkpoint inhibitor treatment for the treatment of nasopharyngeal carcinoma.
  • the subject with recurrent and/or metastatic nasopharyngeal cancer has not previously received immune checkpoint inhibitor therapy for the treatment of recurrent and/or metastatic nasopharyngeal cancer.
  • the subject with advanced nasopharyngeal cancer has not previously received immune checkpoint inhibitor therapy for the treatment of advanced nasopharyngeal cancer.
  • the subject with nasopharyngeal cancer has previously been treated for nasopharyngeal cancer with one or more different anti-tumor treatments (eg, treatment failure or intolerance).
  • the subject with nasopharyngeal cancer has previously received a systemic treatment regimen to treat nasopharyngeal cancer (eg, treatment failure or intolerance).
  • the subject with nasopharyngeal carcinoma has previously received at least one first-line systemic treatment regimen for nasopharyngeal carcinoma (eg, treatment failure or intolerance).
  • the subject with nasopharyngeal carcinoma has previously received neoadjuvant or adjuvant therapy, as well as definitive concurrent chemoradiotherapy to treat nasopharyngeal carcinoma (eg, treatment failure or intolerance).
  • the subject with nasopharyngeal carcinoma has received an immune checkpoint inhibitor for treatment of nasopharyngeal carcinoma at a locally advanced stage (eg, treatment failure or intolerance).
  • the nasopharyngeal cancer is recurrent and/or metastatic nasopharyngeal cancer, and the subject with recurrent and/or metastatic nasopharyngeal cancer has previously received a systemic treatment regimen to treat nasopharyngeal cancer (e.g., , treatment failure or intolerance).
  • a systemic treatment regimen to treat nasopharyngeal cancer e.g., , treatment failure or intolerance
  • the nasopharyngeal cancer is recurrent and/or metastatic nasopharyngeal cancer, and the subject of the recurrent and/or metastatic nasopharyngeal cancer has previously received at least a first-line systemic treatment regimen to treat nasopharyngeal cancer.
  • the nasopharyngeal cancer is recurrent and/or metastatic nasopharyngeal cancer, and the subject of the recurrent and metastatic nasopharyngeal cancer has previously received neoadjuvant therapy or adjuvant therapy, as well as radical concurrent chemoradiotherapy and Treatment of nasopharyngeal carcinoma (e.g., treatment failure or intolerance).
  • the subject with recurrent and/or metastatic nasopharyngeal carcinoma has previously received neoadjuvant or adjuvant therapy, as well as curative concurrent chemoradiotherapy for the treatment of nasopharyngeal carcinoma, and during or withdrew treatment Disease progression within the next 6 months (e.g., 2, 3, 4, 5, or 6 months).
  • the subject with recurrent and/or metastatic nasopharyngeal carcinoma has received an immune checkpoint inhibitor for treatment of nasopharyngeal carcinoma at a locally advanced stage (eg, treatment failure or intolerance).
  • the nasopharyngeal cancer is advanced nasopharyngeal cancer, and the subject with advanced nasopharyngeal cancer has previously received a systemic treatment regimen to treat nasopharyngeal cancer (eg, treatment failure or intolerance).
  • the nasopharyngeal cancer is advanced nasopharyngeal cancer, and the subject with advanced nasopharyngeal cancer has previously received at least one first-line systemic treatment regimen to treat nasopharyngeal cancer (e.g., treatment failure or intolerance) .
  • the nasopharyngeal cancer is advanced nasopharyngeal cancer
  • the subject with advanced nasopharyngeal cancer has previously received neoadjuvant or adjuvant therapy, as well as curative concurrent chemoradiotherapy to treat nasopharyngeal cancer (e.g., treatment failure or intolerance).
  • the subject with advanced nasopharyngeal carcinoma has previously received neoadjuvant therapy or adjuvant therapy, as well as radical concurrent chemoradiotherapy to treat nasopharyngeal carcinoma, and during treatment or within 6 months after stopping treatment (e.g. 2, 3, 4, 5 or 6 months) disease progression.
  • the subject with nasopharyngeal carcinoma has previously been treated for nasopharyngeal carcinoma (eg, treatment failure or intolerance) with one or more of radiation therapy, chemotherapy, and immunotherapy.
  • the subject with nasopharyngeal carcinoma has previously received a platinum-based antineoplastic agent to treat nasopharyngeal carcinoma (eg, treatment failure).
  • the subject with nasopharyngeal carcinoma has previously received an immune checkpoint (eg, PD-1 or PD-L1) inhibitor to treat nasopharyngeal carcinoma (eg, treatment failure or intolerance).
  • an immune checkpoint eg, PD-1 or PD-L1
  • the subject with nasopharyngeal carcinoma has previously received a platinum-based antineoplastic agent and an immune checkpoint (e.g., PD-1 or PD-L1) inhibitor to treat nasopharyngeal carcinoma (e.g., treatment failed or failed). tolerate).
  • a platinum-based antineoplastic agent and an immune checkpoint e.g., PD-1 or PD-L1
  • an immune checkpoint e.g., PD-1 or PD-L1
  • the nasopharyngeal cancer is nasopharyngeal cancer that has failed immune checkpoint inhibitor treatment.
  • the nasopharyngeal carcinoma is recurrent and/or metastatic nasopharyngeal carcinoma that has failed immune checkpoint inhibitor therapy.
  • the nasopharyngeal cancer is advanced nasopharyngeal cancer that has failed immune checkpoint inhibitor therapy.
  • the nasopharyngeal carcinoma is recurrent and/or metastatic nasopharyngeal carcinoma
  • the subject of the recurrent and/or metastatic nasopharyngeal carcinoma has previously received platinum-based anti-tumor drugs and immune checkpoints ( For example, PD-1 or PD-L1) inhibitors to treat nasopharyngeal carcinoma (e.g., treatment failure or intolerance).
  • platinum-based anti-tumor drugs and immune checkpoints For example, PD-1 or PD-L1
  • PD-1 or PD-L1 inhibitors to treat nasopharyngeal carcinoma (e.g., treatment failure or intolerance).
  • the nasopharyngeal carcinoma is recurrent and/or metastatic nasopharyngeal carcinoma
  • the subject of the recurrent and/or metastatic nasopharyngeal carcinoma has previously received platinum-based anti-tumor drugs and immune checkpoints (
  • a PD-1 or PD-L1) inhibitor is used to treat nasopharyngeal carcinoma and the disease progresses during treatment or within 6 months (eg, 2, 3, 4, 5, or 6 months) of stopping treatment.
  • the nasopharyngeal cancer is advanced nasopharyngeal cancer
  • the subject with advanced nasopharyngeal cancer has previously received platinum-based antineoplastic drugs and immune checkpoints (e.g., PD-1 or PD-L1) Inhibitors to treat nasopharyngeal carcinoma (e.g., treatment failure or intolerance).
  • platinum-based antineoplastic drugs and immune checkpoints e.g., PD-1 or PD-L1
  • Inhibitors to treat nasopharyngeal carcinoma e.g., treatment failure or intolerance
  • the nasopharyngeal cancer is advanced nasopharyngeal cancer, and the subject with advanced nasopharyngeal cancer has previously received platinum-based antineoplastic drugs and immune checkpoints (e.g., PD-1 or PD-L1)
  • platinum-based antineoplastic drugs and immune checkpoints e.g., PD-1 or PD-L1
  • An inhibitor is used to treat nasopharyngeal carcinoma and the disease progresses during treatment or within 6 months (e.g., 2, 3, 4, 5, or 6 months) of stopping treatment.
  • the immune checkpoint (e.g., PD-1 or PD-L1) inhibitor is an antibody or antigen-binding fragment thereof directed against an immune checkpoint (e.g., PD-1 or PD-L1), such as: Nivolumab, Pembrolizumab, Toripalimab, Sintilimab, Camrelizumab, Tirelizumab Tislelizumab, Balstilimab, Zimberelimab, Atezolizumab, Durvalumab, Alikumab ( Avelumab), envolimab (Envafolimab) or sugemalimab (Sugemalimab).
  • an immune checkpoint e.g., PD-1 or PD-L1
  • the platinum anti-tumor drugs include, but are not limited to, cisplatin, carboplatin, nedaplatin, bicycloplatin, picoplatin, oxaliplatin, imiplatin, loplatin, loplatin, trinitrate One or more of platinum, phenanthroplatin or sataplatin.
  • the disclosed drug combination and treatment plan have good efficacy in treating nasopharyngeal cancer, especially recurrent and/or metastatic nasopharyngeal cancer. It has a beneficial effect in at least one of ORR, DCR, DOR, PFS, OS, tolerability and side effects.
  • the term "pharmaceutical combination” refers to the simultaneous or sequential administration of two or more active ingredients (including administration as the respective active ingredients themselves, or as their respective pharmaceutically acceptable salts or esters). such as derivatives, prodrugs or compositions).
  • the active ingredients may each be administered to the subject simultaneously as a single formulation, or each as a single formulation sequentially in any order.
  • all of the active ingredients are formulated in a single formulation and administered to the subject simultaneously.
  • part of the active ingredient is formulated in a single formulation and the other parts of the active ingredient are each administered as a single formulation to the subject simultaneously, or sequentially in any order.
  • fixed combination means that the active ingredients are administered simultaneously to a subject in a fixed total dose or dose ratio, or in the form of a single entity, pharmaceutical composition or preparation.
  • non-fixed combination refers to two or more active ingredients as independent entities (such as pharmaceutical compositions, preparations) simultaneously, concurrently or dependently. Sequentially administered to a subject, wherein the active ingredient administered to the subject reaches a therapeutically effective amount. Examples of non-fixed combinations include cocktail therapy, for example, administration of three or more active ingredients. In non-fixed combinations, the individual active ingredients may be packaged, sold or administered as entirely separate pharmaceutical compositions.
  • the "non-fixed combination” also includes the combined use of "fixed combinations" between "fixed combinations” or “fixed combinations” with any one or more independent entities of the active ingredients.
  • antibody refers to an antigen-binding protein having at least one antigen-binding domain.
  • Antibodies and fragments thereof of the present disclosure may be whole antibodies or any fragments thereof.
  • the antibodies and fragments thereof of the present disclosure include monoclonal antibodies or fragments thereof and antibody variants or fragments thereof.
  • Examples of antibodies and antigen-binding fragments thereof include monospecific antibodies, bispecific antibodies, multispecific antibodies, Fab fragments, Fab' fragments, F(ab)' 2 fragments, Fv fragments, isolated CDR regions, single-chain Fv molecules (scFv) and other antibody fragments known in the art.
  • the anti-TIM-3 antibodies and anti-PD-1 antibodies and antigen-binding fragments thereof disclosed herein can be of the IgGl, IgG2, IgG3 or IgG4 isotype.
  • the term "isotype" refers to the class of antibody encoded by the heavy chain constant region genes.
  • the anti-TIM-3 antibodies and antigen-binding fragments thereof and the anti-PD-1 antibodies and antigen-binding fragments thereof of the present disclosure can be derived from any species, including but not limited to mouse, rat, rabbit, primate, llama, and people.
  • anti-TIM-3 antibodies and antigen-binding fragments thereof and the anti-PD-1 antibodies and antigen-binding fragments thereof of the present disclosure may be murine antibodies, chimeric antibodies, humanized antibodies, or fully human antibodies.
  • antibodies in this disclosure include entire antibodies and any antigen-binding fragments (or “antigen-binding portions") or single chains thereof.
  • a conventional "whole antibody” is a glycoprotein containing two heavy (H) chains and two light (L) chains linked by disulfide bonds. Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region (CH).
  • the heavy chain constant region consists of three domains, namely CH1, CH2 and CH3.
  • Each light chain consists of a light chain variable region (VL) and a light chain constant region (CL).
  • the light chain constant region consists of one domain, CL.
  • the VH and VL regions can also be divided into hypervariable regions, namely complementarity determining regions (CDR), and framework regions (FR) with relatively conserved sequences.
  • CDR complementarity determining regions
  • FR framework regions
  • Each VH and VL are composed of three CDRs and four FRs respectively, from the amino end to the carboxyl end: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the variable regions of the heavy and light chains contain binding domains that interact with the antigen.
  • the constant region of an antibody can mediate binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (eg, effector cells) and the first component (Clq) of the classical complement system.
  • various cells of the immune system eg, effector cells
  • Clq first component of the classical complement system.
  • special “whole antibodies”, such as Nanobodies have only heavy (H) chains and no light (L) chains.
  • an “antigen-binding fragment” or “antibody-binding portion” of an antibody refers to one or more fragments of an antibody that retain the function of specifically binding an antigen (eg, TIM-3 or PD-1). It has been demonstrated that the antigen-binding function of an antibody can be performed by fragments of the entire antibody.
  • Examples encompassed by the term "antigen-binding portion/fragment" of an antibody include: (i) Fab fragments: monovalent fragments consisting of VL, VH , CL and CH1 domains; ( ii) F(ab') 2 fragments , a bivalent fragment containing two Fab fragments connected by a disulfide bridge in the hinge region; (iii) an Fd fragment consisting of VH and CH1 domains; (iv) an Fv fragment consisting of the VL and VH domains of an antibody single arm ; (v) a dAb fragment consisting of a VH domain (see Ward et al., Nature.
  • a Nanobody A heavy chain variable region containing a single variable domain and two constant domains.
  • the two domains VL and VH of the Fv fragment are encoded by different genes, recombinant methods can be used to connect VH and VL into a single protein chain through synthetic linkers, in which VL and VH pair to form a monovalent molecule (called a single-chain Fv (scFv); see, for example, Bird et al., Science. 242:423-426 (1988); Huston et al., Proc. Natl. Acad. Sci. 85:5879-5883 (1988)).
  • scFv single-chain Fv
  • antigen-binding portion/fragment single chain antibodies are also encompassed by the term antigen-binding portion/fragment.
  • recombinant polypeptides, fusion proteins and immunoconjugates comprising such antigen-binding portions/fragments are also encompassed by the term antigen-binding portions/fragments.
  • a “chimeric antibody” is an antibody that has at least a portion of a heavy chain variable region derived from one species and at least a portion of a light chain variable region; and at least a portion of a constant region derived from another species.
  • a chimeric antibody may comprise a murine variable region and a human constant region.
  • a “humanized antibody” is an antibody that contains complementarity determining regions (CDRs) derived from a non-human antibody and framework and constant regions derived from a human antibody.
  • CDRs complementarity determining regions
  • anti-TIM-3 antibodies and anti-PD-1 antibodies can comprise CDRs derived from one or more murine antibodies as well as human framework regions and human constant regions.
  • Provided herein are exemplary humanized antibodies. Additional anti-TIM-3 antibodies or variants thereof comprising the HCDR and LCDR provided herein can be generated using any human framework sequences and are also included in the present disclosure. Additional anti-PD-1 antibodies or variants thereof comprising the HCDRs and LCDRs provided herein can be generated using any human framework sequences and are also included in the present disclosure.
  • framework sequences suitable for use in the present disclosure include those that are structurally similar to the framework sequences provided herein. Additional modifications can be made in the framework regions to improve the properties of the antibodies provided herein. Such additional framework modifications may include chemical modifications; point mutations to reduce immunogenicity or remove T cell epitopes; or mutations back to residues in the original germline sequence. In some embodiments, such modifications include those corresponding to mutations exemplified herein, including back mutations to germline sequences. For example, in one embodiment, one or more amino acids in the human framework regions of the VH and/or VL of the humanized antibodies provided herein are backmutated to the corresponding amino acids in the parent murine antibody.
  • identity is also called consistency.
  • Percent (%) identity refers to the sequence to be compared after aligning it with the specific amino acid sequence shown herein and introducing gaps if necessary to achieve the maximum percent sequence identity, and without regard to When any conservative substitution is included as part of sequence identity, the percentage of amino acid residues in the aligned sequence that are identical to the amino acid residues of the specific amino acid sequence shown herein. Alignment of amino acid sequences for identity can be performed using various methods within the scope of the art, such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. One skilled in the art can determine the appropriate parameters for aligning sequences, including any algorithms needed to obtain maximal alignment over the full length of the compared sequences.
  • treatment refers to an attempt to alter the natural course of a disease in a treated individual, and may be for the purpose of preventing, ameliorating, or eliminating the disease or one or more symptoms associated with said disease, including, but not limited to, preventing the occurrence or recurrence of the disease, alleviation Symptoms, reduction of any direct or indirect pathological consequences of the disease, prevention of metastasis, slowing the rate of disease progression, amelioration or alleviation of the disease state, and regression or improved prognosis.
  • the term "effective amount” means (i) treating a specified disease, condition, or disorder, (ii) reducing, ameliorating, or eliminating one or more symptoms of a specified disease, condition, or disorder, or (iii) preventing or delaying the symptoms described herein.
  • the amount of active material e.g., an antibody or antigen-binding fragment thereof of the present disclosure
  • a “therapeutically effective amount” may vary depending on factors such as the disease state, age, sex, and weight of the individual, as well as the therapeutic agent or combination of therapeutic agents. The ability in an individual to elicit a desired response. Effective amounts can also be routinely determined by those skilled in the art based on their own knowledge and this disclosure.
  • a “first treatment phase” is the initial treatment phase, which may be an induction treatment phase
  • a “second treatment phase” is the treatment phase subsequent to the initial treatment phase, which may be a maintenance treatment phase.
  • administering means the physical introduction of a composition comprising a therapeutic agent to a subject using any of a variety of methods and delivery systems known to those skilled in the art.
  • Routes of administration of the antibody or antigen-binding fragment thereof include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other gastric Parenteral route of administration, such as by injection or infusion.
  • parenteral administration refers to modes of administration other than enteral administration, usually by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional , intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion, and in vivo Electroporation. Administration may also be performed, eg, once, multiple times, and/or over one or more extended time periods.
  • flat dose is used to mean the dose administered to a patient without regard to the patient's weight or body surface area (BSA).
  • a unified dose is therefore stated as an absolute amount of agent (eg, anti-TIM-3 antibody or antigen-binding fragment thereof or anti-PD-1 antibody or antigen-binding fragment thereof) rather than as a mg/kg dose.
  • agent eg, anti-TIM-3 antibody or antigen-binding fragment thereof or anti-PD-1 antibody or antigen-binding fragment thereof
  • mg/kg dose e.g, a 60 kg human and a 100 kg human will receive the same dose of antibody (eg, 1200 mg or 1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof; another example, 200 mg of an anti-PD-1 antibody or antigen-binding fragment thereof).
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without multiple toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • the terms "subject,” “patient,” or “subject” are used interchangeably.
  • the subject, patient or subject is a mammal.
  • the subject, patient or subject is a mouse.
  • the subject, patient or subject is a human.
  • “about” means within the range of error that one of ordinary skill in the art would determine is acceptable for a particular value, which depends in part on how the value is measured or determined, ie, the limitations of the measurement system. For example, “about” may mean within 1 or more than 1 standard deviation in accordance with practice in the art. Alternatively, “about” may mean up to ⁇ 5%, such as ⁇ 2%, ⁇ 1%, or ⁇ 0.5% of a given numerical range. When a specific value is given in the disclosure or claims, unless otherwise stated, the meaning of "about” shall be considered to be within an acceptable error range for that specific value. In this document, all values of drug dosage, time, step parameter or condition are modified by “about” by default unless stated otherwise.
  • “combination” or “used in combination” means that two or more active substances may be administered to a subject simultaneously, each as a single formulation, or each as a single formulation, sequentially in any order. Alternatively, all of the active substances are formulated in a single formulation and administered to the subject simultaneously. Alternatively, part of the active substance is formulated in a single formulation and the other parts of the active substance are each administered as a single preparation to the subject simultaneously, or sequentially in any order.
  • single dose refers to the smallest packaging unit containing a certain amount of medicine. For example, if a box of medicine contains seven tablets, one tablet is a single dose; or a bottle of injection is a single dose.
  • multiple doses consists of a plurality of single doses.
  • unit dose refers to the dose of active ingredient contained in the smallest packaging unit containing a certain amount of medicine.
  • dose of antibody contained in a bottle of antibody injection is a unit dose.
  • recurrent cancer is a cancer that regenerates at the original site or at a distant site after responding to initial treatment (eg, surgery).
  • metalstatic cancer refers to cancer that has spread from one part of the body (such as the nasopharyngeal cavity) to another part of the body.
  • treatment failure is defined as disease progression or recurrence during treatment or after the last treatment.
  • a “line of therapy” refers to a position in a sequence in which a patient receives different medications or other treatments.
  • first-line treatment refers to the first or standard choice of drug treatment based on the patient's condition.
  • Embodiment 1 A pharmaceutical combination comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the anti-TIM-3 antibody or an antigen-binding fragment thereof comprises:
  • HCDR1 with the amino acid sequence shown in SEQ ID NO:21
  • HCDR2 with the amino acid sequence shown in SEQ ID NO:22
  • HCDR3 with the amino acid sequence shown in SEQ ID NO:23
  • LCDR1 with the amino acid sequence shown in SEQ ID NO:24
  • LCDR2 with the amino acid sequence shown in SEQ ID NO:25
  • LCDR3 with the amino acid sequence shown in SEQ ID NO:26.
  • Embodiment 2 The pharmaceutical combination according to Embodiment 1, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof comprises:
  • Embodiment 3 The pharmaceutical combination according to embodiment 1 or 2, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof comprises:
  • Embodiment 4 The pharmaceutical combination according to any one of embodiments 1-3, wherein the unit dose of the anti-TIM-3 antibody or antigen-binding fragment thereof is 60-1800 mg, 100-1600 mg, 120-1600 mg, 180-1200 mg, or 240-600 mg; preferably, the unit dose of the anti-TIM-3 antibody or antigen-binding fragment thereof is 240 mg, 300 mg, 360 mg and/or 600 mg.
  • Embodiment 5 The pharmaceutical combination according to any one of embodiments 1-4, wherein the unit dose of the anti-PD-1 antibody or antigen-binding fragment thereof is 10-500 mg, 50-500 mg, 50-200 mg, Or 100-200 mg; preferably, the unit dose of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg and/or 200 mg.
  • Embodiment 6 The pharmaceutical combination according to any one of embodiments 1-5, wherein the mass ratio of the anti-TIM-3 antibody or antigen-binding fragment thereof: the anti-PD-1 antibody or antigen-binding fragment thereof is ( 0.1-180):1, (0.2-50):1, (0.5-9):1, (3-7.5):1, (4-7.5):1 or (6-7.5):1.
  • Embodiment 7 The pharmaceutical combination according to any one of embodiments 1-6, wherein the pharmaceutical combination is suitable for use in a single treatment week Administration within a period, which includes 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg of anti-TIM-3 antibody or antigen-binding fragment thereof; preferably, the pharmaceutical combination is suitable for administration within a single treatment cycle, It includes 1200 mg or 1500 mg of anti-TIM-3 antibody or antigen-binding fragment thereof; more preferably, the pharmaceutical combination is suitable for administration in a single treatment cycle and includes 1200 mg of anti-TIM-3 antibody or antigen-binding fragment thereof.
  • Embodiment 8 The pharmaceutical combination according to Embodiment 7, wherein the pharmaceutical combination further includes 10-800 mg, 50-500 mg, or 100-200 mg of anti-PD-1 antibody or antigen-binding fragment thereof; preferably, the pharmaceutical combination The drug combination also includes 200 mg of anti-PD-1 antibody or antigen-binding fragment thereof.
  • Embodiment 9 The pharmaceutical combination according to any one of embodiments 1-8, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises: HCDR1 of the amino acid sequence shown in SEQ ID NO: 11, SEQ ID HCDR2 with the amino acid sequence shown in NO:12, HCDR3 with the amino acid sequence shown in SEQ ID NO:13, LCDR1 with the amino acid sequence shown in SEQ ID NO:14, LCDR2 with the amino acid sequence shown in SEQ ID NO:15, and SEQ ID NO : LCDR3 with the amino acid sequence shown in 16.
  • Embodiment 10 The pharmaceutical combination according to any one of embodiments 1-9, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises: an amino acid sequence having at least the same amino acid sequence as that shown in SEQ ID NO: 17 A heavy chain variable region that is 95% identical, and a light chain variable region that has an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 18.
  • Embodiment 11 The pharmaceutical combination according to any one of embodiments 1-10, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises: an amino acid sequence having at least the same amino acid sequence as that shown in SEQ ID NO: 19 A heavy chain that is 95% identical, and a light chain that has an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO:20.
  • Embodiment 12 The pharmaceutical combination according to any one of embodiments 1-11, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof and/or the anti-PD-1 antibody or antigen-binding fragment thereof is formulated with Preparations for parenteral administration, preferably, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody and/or antigen-binding fragment thereof are formulated for intravenous, intramuscular or subcutaneous administration preparation.
  • Embodiment 13 The pharmaceutical combination according to any one of embodiments 1-12, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are formulated separately.
  • Embodiment 14 The pharmaceutical combination according to any one of embodiments 1-13, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are formulated in a single formulation .
  • Embodiment 15 A pharmaceutical combination, which includes the pharmaceutical combination according to any one of embodiments 1-14 and a chemotherapeutic drug.
  • Embodiment 16 The drug combination according to Embodiment 15, wherein the chemotherapy drug is a platinum-based anti-tumor drug and/or an antimetabolite anti-tumor drug;
  • the platinum anti-tumor drug is selected from the group consisting of cisplatin, carboplatin, nedaplatin, bicycloplatin, picoplatin, oxaliplatin, imiplatin, loplatin, loplatin, triplatinum tetranitrate, phenanthroplatin or one or more of sataplatin;
  • the antimetabolite anti-tumor drug is selected from one or more of cytarabine, gemcitabine, azacitidine, and amcitabine.
  • Embodiment 17 The drug combination according to embodiment 16, wherein the chemotherapy drug is cisplatin and gemcitabine.
  • Embodiment 18 The pharmaceutical combination according to embodiment 17, wherein the unit dose of gemcitabine is 0.2g and/or 1.0g, and the unit dose of cisplatin is 2.5 mg, 5 mg, 10 mg, 20 mg, 25 mg, 30 mg , 50mg and/or 100mg.
  • Embodiment 19 The pharmaceutical combination according to embodiment 17 or 18, wherein the pharmaceutical combination is suitable for administration within a single treatment cycle, the dosage of gemcitabine is 1.0-2.0 g/m 2 and the dosage of cisplatin It is 40-80mg/m 2 or 40-75mg/m 2 .
  • Embodiment 20 Use of the pharmaceutical combination of any one of embodiments 1-14 for the preparation of a medicament for treating tumors in a subject.
  • Embodiment 21 The use according to embodiment 20, wherein the tumor is a solid tumor; optionally, the solid tumor is nasopharyngeal carcinoma.
  • Embodiment 22 The use according to embodiment 20 or 21, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof can be administered simultaneously, sequentially and/or alternately. medicine.
  • Embodiment 23 The use according to embodiment 22, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are administered sequentially.
  • Embodiment 24 The use of any one of embodiments 20-23, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof is administered every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks Once; optionally, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered at a dose of 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg each time; preferably, the anti-TIM-3 The antibody or antigen-binding fragment thereof is administered at a dose of 1200 mg or 1500 mg each time; more preferably, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered at a dose of 1200 mg or 1500 mg each time. Administered at a dose of 1200 mg.
  • Embodiment 25 The use of any one of embodiments 20-24, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks Once; optionally, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 10-800 mg, 50-500 mg, or 100-200 mg each time; preferably, the anti-PD-1 antibody or antigen thereof The binding fragments were administered in doses of 200 mg each time.
  • Embodiment 26 Use of the pharmaceutical combination of any one of embodiments 15-19 for the preparation of a medicament for treating tumors in a subject.
  • Embodiment 27 The use of embodiment 26, wherein the tumor is a solid tumor; optionally, the solid tumor is nasopharyngeal carcinoma.
  • Embodiment 28 The use according to embodiment 26 or 27, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof, anti-PD-1 antibody or antigen-binding fragment thereof, cisplatin and gemcitabine can be administered simultaneously or sequentially. and/or alternate dosing.
  • Embodiment 29 The use of any one of embodiments 26-28, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof is administered every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks Once; optionally, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered at a dose of 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg each time; preferably, the anti-TIM-3 The antibody or antigen-binding fragment thereof is administered at a dose of 1200 mg or 1500 mg each time; more preferably, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered at a dose of 1200 mg each time.
  • Embodiment 30 The use of any one of embodiments 26-29, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks Once; optionally, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 10-800 mg, 50-500 mg, or 100-200 mg each time; preferably, the anti-PD-1 antibody or antigen thereof The binding fragments were administered in doses of 200 mg each time.
  • Embodiment 31 The use of any one of embodiments 26-30, wherein the cisplatin is administered every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks; optionally, the Cisplatin is administered at a dose of 40-80 mg/m 2 or 40-75 mg/m 2 each time; preferably, the cisplatin is administered at a dose of 40 mg/m 2 , 60 mg/m 2 , 75 mg/m 2 , or 80 mg/m 2 each time. A dose of m 2 was administered.
  • Embodiment 32 The use of any one of embodiments 26-31, wherein the gemcitabine is administered twice every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks; optionally, the Gemcitabine is administered at a dose of 0.5-1.0 g/m 2 each time; preferably, gemcitabine is administered at a dose of 0.5 g/m 2 , 0.75 g/m 2 or 1.0 g/m 2 each time.
  • Embodiment 33 A method of treating a tumor in a subject, wherein the method comprises administering to the subject an effective amount of the pharmaceutical combination of any one of embodiments 1-19.
  • Embodiment 34 A method of treating tumors in a subject, wherein the method comprises administering to the subject an effective amount of the pharmaceutical combination of any one of embodiments 15-19 in a first treatment phase, And in the second treatment phase, an effective amount of the pharmaceutical combination described in any one of embodiments 1-14 is administered to the subject.
  • Embodiment 35 The method according to embodiment 34, wherein the treatment cycles of the first treatment phase include 1-14 treatment cycles, 2-12 treatment cycles or 2-10 treatment cycles, preferably 2-14 treatment cycles. 8 treatment cycles, more preferably 4-6 treatment cycles.
  • Embodiment 36 The method of any one of embodiments 33-35, wherein the tumor is a solid tumor; optionally, the solid tumor is nasopharyngeal carcinoma.
  • Embodiment 37 A kit for treating tumors, comprising the pharmaceutical combination according to any one of embodiments 1-19; optionally, the tumor is a solid tumor; optionally, the solid tumor For nasopharyngeal cancer.
  • Embodiment 38 A combined pharmaceutical combination, comprising:
  • Embodiment 39 The combined drug combination according to embodiment 38, wherein the treatment cycle of the first treatment stage includes 1-14 treatment cycles, 2-12 treatment cycles or 2-10 treatment cycles, preferably It is 2-8 treatment cycles, more preferably 4-6 treatment cycles.
  • Embodiment 40 Use of the combined drug combination of embodiment 39 in the preparation of a medicament for treating tumors in a subject.
  • Embodiment 41 The use of embodiment 40, wherein the tumor is a solid tumor; optionally, the solid tumor is nasopharyngeal carcinoma.
  • Example 1 Clinical trial of nasopharyngeal carcinoma
  • nasopharyngeal cancer confirmed by histology or cytology, stage IVb as defined by the 2017 8th edition of the AJCC nasopharyngeal carcinoma TNM staging system, or recurrent nasopharyngeal cancer not suitable for local treatment
  • Subjects for neoadjuvant/adjuvant therapy, radical concurrent chemoradiotherapy, if the disease progresses during treatment or within 6 months after stopping treatment, it should be counted as a failure of the first-line treatment of the original plan, if it exceeds 6 months, it cannot be counted Failure of first-line treatment. All changes in treatment plan due to drug intolerance are not counted as treatment failure):
  • Platinum-containing chemotherapy and immune checkpoint inhibitors have failed treatment and have evidence of imaging progression that meets RECIST 1.1 standards.
  • Platinum-containing chemotherapy and immune checkpoint inhibitors have failed Treatment can be during palliative treatment for recurrence/metastasis or during curative treatment for locally advanced disease;
  • Immunotherapy for recurrence/metastasis does not exceed the second line.
  • neoadjuvant/adjuvant treatment radical concurrent chemoradiotherapy, if the disease progresses during treatment or within 6 months after stopping treatment, it should be counted as the first line of the original plan.
  • Treatment failure if it exceeds 6 months, cannot be counted as first-line treatment failure. All changes in the treatment plan due to drug intolerance are not counted as treatment failure);
  • the best efficacy during the induction phase is at least PR;
  • Routine blood examination standards no blood transfusion or correction with hematopoietic stimulating factor drugs within 14 days before the examination:
  • ALT Alanine aminotransferase
  • AST aspartate aminotransferase
  • APTT Activated partial thrombin time
  • ILR international normalized ratio
  • PT prothrombin time
  • Thyroid function tests must meet the following standards:
  • TSH Thyroid-stimulating hormone
  • LVEF left ventricular ejection fraction
  • Female subjects of childbearing age should agree to use contraceptive measures (such as intrauterine devices, birth control pills or condoms) during the study period and within 6 months after the end of the study; serum pregnancy / The urine pregnancy test is negative and must be non-lactating subjects; male subjects must agree to use contraceptive measures during the study period and within 6 months after the end of the study period.
  • contraceptive measures such as intrauterine devices, birth control pills or condoms
  • the anti-PD-1 antibody injection is infused first, and then the anti-TIM-3 antibody injection is infused.
  • Anti-PD-1 antibody injection (specification: 100mg/10mL/bottle): every 3 weeks is a treatment cycle (administration time window: ⁇ 3 days), through intravenous infusion, starting from the first day of each treatment cycle A dose of 200 mg of anti-PD-1 antibody is administered once (i.e., 200 mg, d1/Q3W).
  • Anti-TIM-3 antibody injection (specification: 240mg/4mL/bottle, or 600mg/10mL/bottle): every 3 weeks is a treatment cycle (administration time window: ⁇ 3 days), via intravenous infusion, every A dose of 1200 mg or 1500 mg of anti-TIM-3 antibody was administered once on day 1 of each treatment cycle (i.e. 1200 mg or 1500 mg, d1/Q3W).
  • Gemcitabine hydrochloride injection starting dose is 1g/m 2 , administered on the 1st and 8th day of each treatment cycle.
  • Cisplatin injection starting dose is 75 mg/m 2 , administered on the first day of each treatment cycle.
  • Anti-TIM-3 antibody injection (1200mg, d1/Q3W) + anti-PD-1 antibody injection (200mg, d1/Q3W) + GP chemotherapy regimen (gemcitabine + cisplatin) induction therapy for 4-6 treatments
  • anti-TIM-3 antibody injection (1200 mg, d1/Q3W) + anti-PD-1 antibody injection (200 mg, d1/Q3W) maintenance treatment.
  • the efficacy evaluation standard is based on RECIST 1.1, and the iRECIST standard is used to confirm the efficacy.
  • ORR Objective response rate
  • CRR complete response rate
  • DCR disease control rate
  • DOR duration of response
  • PFS progression-free survival
  • OS overall survival
  • Adverse event incidence the occurrence of all adverse events (AE), serious adverse events (SAE) and treatment-related adverse events (TRAEs), as well as abnormal laboratory test indicators.
  • Target lesion size and assessment results are as follows:
  • target lesion 34mm
  • target lesion 28 mm
  • target lesion 25mm
  • target lesion 21mm
  • target lesion 22 mm.
  • the patient's best efficacy is PR.
  • Target lesion size and assessment results are as follows:
  • target lesion 41mm
  • target lesion 28 mm
  • target lesion 19 mm
  • target lesion 17 mm
  • target lesion 18mm.
  • the patient's best efficacy is PR.
  • anti-TIM-3 antibody injection + anti-PD-1 antibody injection + GP chemotherapy regimen After 4 cycles of induction treatment with anti-TIM-3 antibody injection + anti-PD-1 antibody injection + GP chemotherapy regimen, anti-TIM-3 antibody injection + anti-PD-1 antibody injection was used as maintenance treatment.
  • Target lesion size and assessment results are as follows:
  • target lesion 30.5mm
  • target lesion 20.3mm
  • target lesion 19.4mm
  • target lesion 19.2mm
  • target lesion 15.3mm.
  • the patient's best efficacy is PR.
  • Target lesion size and assessment results are as follows:
  • target lesion 35mm
  • target lesion 15 mm
  • target lesion 14mm.
  • the patient's best efficacy is PR.
  • Target lesion size and assessment results are as follows:
  • target lesion 112.36mm
  • target lesion 77.2mm
  • target lesion 66.4mm
  • target lesion 65.2mm.
  • the patient's best efficacy is PR.
  • Target lesion size and assessment results are as follows:
  • target lesion 39mm
  • target lesion 19mm
  • target lesion 13.5mm.
  • the patient's best efficacy is PR.
  • Target lesion size and assessment results are as follows:
  • target lesion 17mm
  • target lesion 11mm.
  • the patient's best efficacy is PR.
  • Target lesion size and assessment results are as follows:
  • target lesion 84mm
  • target lesion 34mm.
  • the patient's best efficacy is PR.
  • Treatment plan anti-TIM-3 antibody injection + anti-PD-1 antibody injection + GP chemotherapy regimen induction therapy for 3 cycles.
  • Target lesion size and assessment results are as follows:
  • target lesion 53.4mm
  • target lesion 19.7 mm.
  • the patient's best efficacy is PR.

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Abstract

提供结合TIM-3的抗体与结合PD-1的抗体的药物组合，其包括抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段；任选地，还包括化疗药物。还提供用于治疗肿瘤的试剂盒，其包含所述药物组合。此外，还提供所述药物组合在制备用于治疗肿瘤的药物中的用途以及所述药物组合治疗肿瘤的方法。

Description

结合TIM-3的抗体与结合PD-1的抗体的药物组合
本公开要求于2022年09月06日提交中国国家知识产权局专利局、申请号为202211081252.2、发明名称为“结合TIM-3的抗体与结合PD-1的抗体的药物组合”的中国专利申请的优先权，其全部内容通过引用结合在本公开中。
技术领域
本公开属于生物医药领域，具体涉及结合TIM-3的抗体与结合PD-1的抗体的药物组合。
背景技术
近年来肿瘤发病率呈上升趋势，恶性肿瘤治疗效果差，晚期转移率高。目前临床上采用的常规治疗方法如放疗、化疗和手术治疗虽然能够缓解病痛，延长生存时间，但均存在局限。因此通过对免疫检查点的抑制、实现免疫细胞的再次活化、避免肿瘤细胞的免疫逃逸、从而杀伤肿瘤细胞的免疫治疗，已逐渐成为肿瘤治疗领域的热点。
T细胞免疫球蛋白和粘蛋白结构域蛋白3(T cell immunoglobulin and mucin domain-containing protein 3，TIM-3)，也称为甲型肝炎病毒细胞受体2(Hepatitis A Virus Cellular Receptor 2，HAVCR2)，是免疫调节蛋白TIM家族成员(人TIM家族包括TIM-1、3、4)，TIM-3选择性地表达于活化的Th1细胞表面，还在髓细胞、DC细胞、NK细胞、巨噬细胞上表达，同时也在多种肿瘤细胞上表达。TIM-3具有多种不同的配体，包括半乳凝素9(Galectin9)、磷酯酰丝氨酸(PtdSer)、高迁移族蛋白B1(HMGB1)和癌胚抗原细胞黏附分子1(CEACAM1)。TIM-3作为一种免疫检查点，其生理功能为负向调节机体的免疫作用，避免过强的免疫作用或自身免疫作用对机体的损伤。越来越多的证据表明，TIM-3蛋白和/或mRNA在多种肿瘤组织和肿瘤相关的免疫细胞上表达上调，参与肿瘤免疫逃逸和免疫应答，促进肿瘤的发展。
PD-1(Programmed death-1，程序性死亡受体1)是一种由活化的T淋巴细胞和B淋巴细胞表达的关键免疫检查点受体并介导免疫抑制，其配体包括PD-L1和PD-L2。中国专利文献CN106977602A公开了一种抗PD-1单克隆抗体14C12H1L1，该单克隆抗体能够有效地阻断PD-1与PD-L1的结合，显示出较好的抗肿瘤活性。
将抗TIM-3抗体与抗PD-1抗体联合，可以共同阻断TIM-3和PD-1的信号通路，提高抗肿瘤效果。
发明概述
在一方面，本公开提供一种药物组合，其包括抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段；任选地，还包括化疗药物。在一些实施方案中，所述化疗药物为铂类抗肿瘤药物和/或抗代谢类抗肿瘤药物。在一些实施方案中，所述化疗药物为铂类抗肿瘤药物和/或胞嘧啶类抗肿瘤药物。在一些实施方案中，所述化疗药物为顺铂和吉西他滨。
在一些实施方案中，所述药物组合包括单位剂量为60-1800mg的抗TIM-3抗体或其抗原结合片段和单位剂量为10-500mg的抗PD-1抗体或其抗原结合片段。在一些实施方案中，所述药物组合包括单位剂量为60-1800mg的抗TIM-3抗体或其抗原结合片段、单位剂量为10-500mg的抗PD-1抗体或其抗原结合片段和化疗药物。在一些实施方案中，所述药物组合包括单位剂量为60-1800mg的抗TIM-3抗体或其抗原结合片段、单位剂量为10-500mg的抗PD-1抗体或其抗原结合片段、和单位剂量为2.5-100mg的顺铂和单位剂量为0.2-1.0g的吉西他滨。
在一些实施方案中，所述药物组合包括100-1800mg的抗TIM-3抗体或其抗原结合片段和10-800mg的抗PD-1抗体或其抗原结合片段。在一些实施方案中，所述药物组合包括100-1800mg的抗TIM-3抗体或其抗原结合片段、10-800mg的抗PD-1抗体或其抗原结合片段和化疗药物。在一些实施方案中，所述药物组合包括100-1800mg的抗TIM-3抗体或其抗原结合片段、10-800mg的抗PD-1抗体或其抗原结合片段、40-80mg/m2的顺铂和0.5-1.0g/m2的吉西他滨。
在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，其包括100-1800mg的抗TIM-3抗 体或其抗原结合片段和10-800mg的抗PD-1抗体或其抗原结合片段。在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，其包括100-1800mg的抗TIM-3抗体或其抗原结合片段、10-800mg的抗PD-1抗体或其抗原结合片段和化疗药物。在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，其包括100-1800mg的抗TIM-3抗体或其抗原结合片段、10-800mg的抗PD-1抗体或其抗原结合片段、40-80mg/m2的顺铂和1.0-2.0g/m2的吉西他滨。
在一些实施方案中，所述药物组合用于治疗肿瘤。
在另一方面，本公开还提供在受试者中治疗肿瘤的方法，其包括向受试者给予有效量的本公开的药物组合。另外，本公开还提供了本公开的药物组合在制备用于治疗受试者中肿瘤的药物中的用途。另外，本公开还提供了本公开的药物组合在制备用于一线治疗受试者中肿瘤的药物中的用途。另外，本公开还提供了本公开的药物组合治疗受试者中肿瘤的用途。另外，本公开还提供了本公开的药物组合一线治疗受试者中肿瘤的用途。在一些实施方案中，在所述方法或用途中，其包括向受试者给予有效量的本公开的药物组合。在一些实施方案中，在所述方法或用途中，包括在第一治疗阶段向受试者给予有效量的本公开的药物组合，并且在第二治疗阶段向受试者给予有效量的本公开的药物组合。
在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段，可同时、先后和/或交替给药。
在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段和化疗药物，可同时、先后和/或交替给药。在一些实施方案中，所述化疗药物为铂类抗肿瘤药物和/或抗代谢类抗肿瘤药物。在一些实施方案中，所述化疗药物为铂类抗肿瘤药物和/或胞嘧啶类抗肿瘤药物。在一些实施方案中，所述化疗药物为顺铂和吉西他滨。
在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段每1周、每2周、每3周、或每4周施用一次。在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段每次以100-1800mg的剂量施用。
在一些实施方案中，所述抗PD-1抗体或其抗原结合片段每1周、每2周、每3周、或每4周施用一次。在一些实施方案中，所述抗PD-1抗体或其抗原结合片段每次以10-800mg的剂量施用。
在一些实施方案中，所述顺铂每1周、每2周、每3周、或每4周施用一次。在一些实施方案中，所述顺铂每次以40-80mg/m2的剂量施用。
在一些实施方案中，所述吉西他滨每1周、每2周、每3周、或每4周施用二次。在一些实施方案中，所述吉西他滨每次以0.5-1.0g/m2的剂量施用。
在另一方面，本公开提供用于治疗肿瘤的试剂盒，其包括本公开的药物组合。在一些实施方案中，所述试剂盒包括抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段；任选地，还包括化疗药物。在一些实施方案中，所述化疗药物为铂类抗肿瘤药物和/或抗代谢类抗肿瘤药物。在一些实施方案中，所述化疗药物为铂类抗肿瘤药物和/或胞嘧啶类抗肿瘤药物。在一些实施方案中，所述化疗药物为顺铂和吉西他滨。
此外，本公开还提供用于治疗肿瘤的抗TIM-3抗体或其抗原结合片段。本公开还提供在受试者中治疗肿瘤的方法，包括向受试者给予有效量的本公开的抗TIM-3抗体或其抗原结合片段。本公开还提供抗TIM-3抗体或其抗原结合片段在制备用于治疗受试者中肿瘤的药物中的用途。本公开还提供抗TIM-3抗体或其抗原结合片段治疗肿瘤的用途。
在一些实施方案中，所述肿瘤为实体瘤。在一些实施方案中，所述肿瘤为鼻咽癌。
发明详述
药物组合
在一方面，本公开提供一种药物组合，其包括抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段；任选地，还包括化疗药物。
在一些实施方案中，所述化疗药物包括但不限于铂类抗肿瘤药物、紫杉烷类抗肿瘤药物、抗代谢类抗肿瘤药物、喜树碱类抗肿瘤药物、氮芥类抗肿瘤药物、蒽环类抗肿瘤药物、长春碱类抗肿瘤药物、鬼臼生物碱类抗肿瘤药物、和激素类抗肿瘤药物中一种或多种。在一些实施方案中，所述化疗药物为铂类抗肿瘤药物和/或抗代谢类抗肿瘤药物。在一些实施方案中，所述化疗药物为铂类抗肿瘤药物和/或胞嘧啶类抗肿 瘤药物。在一些具体实施方案中，所述化疗药物为顺铂和吉西他滨。
在一些实施方案中，所述药物组合包括抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段。在一些实施方案中，所述药物组合包括抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段和化疗药物。在一些实施方案中，所述药物组合包括抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段、铂类抗肿瘤药物和抗代谢类抗肿瘤药物。在一些实施方案中，所述药物组合包括抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段、铂类抗肿瘤药物和胞嘧啶类抗肿瘤药物。在一些实施方案中，所述药物组合包括抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段、顺铂和吉西他滨。
此外，本公开还提供了一种联用药物组合，其包含：
(a)本公开的药物组合，其被制备为适合在第一治疗阶段向受试者给予；和
(b)本公开的药物组合，其被制备为适合在第二治疗阶段向受试者给予。
在一些实施方案中，所述联用药物组合包含：
(a)包括抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段和化疗药物的药物组合，其被制备为适合在第一治疗阶段向受试者给予；和
(b)包括抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段的药物组合，其被制备为适合在第二治疗阶段向受试者给予。
在一些实施方案中，所述联用药物组合包含：
(a)包括抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段、铂类抗肿瘤药物和抗代谢类抗肿瘤药物的药物组合，其被制备为适合在第一治疗阶段向受试者给予；和
(b)包括抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段的药物组合，其被制备为适合在第二治疗阶段向受试者给予。
在一些实施方案中，所述联用药物组合包含：
(a)包括抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段、铂类抗肿瘤药物和胞嘧啶类抗肿瘤药物的药物组合，其被制备为适合在第一治疗阶段向受试者给予；和
(b)包括抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段的药物组合，其被制备为适合在第二治疗阶段向受试者给予。
在一些实施方案中，所述联用药物组合包含：
(a)包括抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段、顺铂和吉西他滨的药物组合，其被制备为适合在第一治疗阶段向受试者给予；和
(b)包括抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段的药物组合，其被制备为适合在第二治疗阶段向受试者给予。
在一些实施方案中，所述第一治疗阶段的治疗周期包括1-14个治疗周期，优选2-12个治疗周期、2-10个治疗周期，更优选2-8个治疗周期，例如：2-8个治疗周期，3-8个治疗周期，4-8个治疗周期，2-7个治疗周期，3-7个治疗周期，4-7个治疗周期，2-6个治疗周期，3-6个治疗周期，或4-6个治疗周期；最优选4-6个治疗周期，例如：4个治疗周期，5个治疗周期，和/或6个治疗周期。
在一些实施方案中，每1周、每2周、每3周、或每4周为一个治疗周期。在一些实施方案中，每3周为一个治疗周期。
在一些实施方案中，所述第二治疗阶段在第一治疗阶段之后。在一些实施方案中，所述第二治疗阶段是从第一治疗阶段结束后持续直到失去临床获益、毒性不可耐受、疗效评价为疾病进展(PD)、和/或研究者认为不适合继续用药。
在一些实施方案中，所述药物组合包装于同一试剂盒中，所述试剂盒还包括将抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段联合使用以治疗肿瘤的说明。在另一些实施方案中，所述药物组合中的抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段分开包装于各自的药盒中，所述药盒还包括将抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段联合使用以治疗肿瘤的说明。
在一些实施方案中，所述药物组合包装于同一试剂盒中，所述试剂盒还包括将抗TIM-3抗体或其抗原 结合片段、抗PD-1抗体或其抗原结合片段和化疗药物(例如，顺铂和吉西他滨)联合使用以治疗肿瘤的说明。在另一些实施方案中，所述药物组合中的抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段和化疗药物(例如，顺铂和吉西他滨)分开包装于各自的药盒中，所述药盒还包括将抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段和化疗药物(例如，顺铂和吉西他滨)联合使用以治疗肿瘤的说明。
在一些实施方案中，所述药物组合是固定组合。在一些实施方案中，所述固定组合呈固体药物组合物的形式或液体药物组合物的形式。
在一些实施方案中，所述药物组合是非固定组合。在一些实施方案中，所述非固定组合中的抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段各自呈药物组合物的形式。在一些实施方案中，所述非固定组合中的抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段和化疗药物(例如，顺铂和吉西他滨)各自呈药物组合物的形式。
在一些具体实施方案中，所述非固定组合中，含抗TIM-3抗体或其抗原结合片段的药物组合物为液体药物组合物或固体药物组合物。在一些具体实施方案中，所述含抗TIM-3抗体或其抗原结合片段的药物组合物为注射液。在一些具体实施方案中，所述含抗TIM-3抗体或其抗原结合片段的药物组合物为冻干制剂。
在一些具体实施方案中，所述非固定组合中，含抗PD-1抗体或其抗原结合片段的药物组合物为液体药物组合物或固体药物组合物。在一些具体实施方案中，所述含抗PD-1抗体或其抗原结合片段的药物组合物为注射液。在一些具体实施方案中，所述含抗PD-1抗体或其抗原结合片段的药物组合物为冻干制剂。
在一些具体实施方案中，所述非固定组合中，抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段配制在单一制剂中。在一些实施方案中，所述非固定组合中，含抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段的药物组合物为液体药物组合物或固体药物组合物。在一些具体实施方案中，含抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段的药物组合物为注射液。在一些具体实施方案中，含抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段的药物组合物为冻干制剂。
在一些具体实施方案中，所述非固定组合中，含化疗药物的药物组合物为液体药物组合物或固体药物组合物。在一些具体实施方案中，含顺铂的药物组合物为液体药物组合物或固体药物组合物。在一些具体实施方案中，含吉西他滨的药物组合物为液体药物组合物或固体药物组合物。在一些具体实施方案中，所述含顺铂的药物组合物为注射液。在一些具体实施方案中，所述含吉西他滨的药物组合物为注射液。本公开的目的还在于提供一种药物包，其在独立的容器中分别包含单包装的药物组合物，其中，在第一个容器中包括含抗TIM-3抗体或其抗原结合片段的药物组合物，在第二个容器中包括含抗PD-1抗体或其抗原结合片段的药物组合物；任选地，还包含一个或多个其他容器，在其他容器中包括含化疗药物(例如，顺铂和吉西他滨)的药物组合物。
在一些实施方案中，所述药物组合中抗TIM-3抗体或其抗原结合片段的单位剂量为60-1800mg、100-1600mg、120-1600mg、180-1200mg、或240-600mg。在一些实施方案中，所述药物组合中抗TIM-3抗体或其抗原结合片段的单位剂量为约60mg、约120mg、约160mg、约180mg、约200mg、约240mg、约280mg、约300mg、约320mg、约360mg、约400mg、约420mg、约440mg、约480mg、约520mg、约540mg、约560mg、约600mg、约640mg、约660mg、约680mg、约720mg、约760mg、约780mg、约800mg、约840mg、约880mg、约900mg、约920mg、约960mg、约1000mg、约1020mg、约1040mg、约1080mg、约1120mg、约1140mg、约1160mg、约1200mg、约1240mg、约1260mg、约1280mg、约1320mg、约1360mg、约1380mg、约1400mg、约1440mg、约1480mg、约1500mg、约1520mg、约1560mg、约1600mg、约1620mg、约1640mg、约1680mg、约1720mg、约1740mg、约1760mg、和/或约1800mg、或者上述任意值形成的范围。在一些实施方案中，所述药物组合中抗TIM-3抗体或其抗原结合片段的单位剂量为约240mg、约300mg、约360mg和/或约600mg。在一些实施方案中，所述药物组合中抗TIM-3抗体或其抗原结合片段的单位剂量为约240mg和/或约600mg。
在一些实施方案中，所述药物组合中抗PD-1抗体或其抗原结合片段的单位剂量为10-500mg、50-500mg、50-200mg、或100-200mg。在一些实施方案中，所述药物组合中抗PD-1抗体或其抗原结合片段的单位剂量为约10mg、约20mg、约30mg、约40mg、约50mg、约60mg、约70mg、约80mg、约90mg、 约100mg、约110mg、约120mg、约130mg、约140mg、约150mg、约160mg、约170mg、约180mg、约190mg、约200mg、约210mg、约220mg、约230mg、约240mg、约250mg、约260mg、约270mg、约280mg、约290mg、约300mg、约310mg、约320mg、约330mg、约340mg、约350mg、约360mg、约370mg、约380mg、约390mg、约400mg、约410mg、约420mg、约430mg、约440mg、约450mg、约460mg、约470mg、约480mg、约490mg、和/或约500mg、或者上述任意值形成的范围。在一些实施方案中，所述药物组合中抗PD-1抗体或其抗原结合片段的单位剂量为约100mg和/或约200mg。在一些实施方案中，所述药物组合中抗PD-1抗体或其抗原结合片段的单位剂量为约100mg。
在一些实施方案中，所述药物组合还包括化疗药物。在一些实施方案中，所述化疗药物为顺铂和吉西他滨。在一些实施方案中，所述药物组合中顺铂的单位剂量为2.5mg、5mg、10mg、20mg、25mg、30mg、50mg和/或100mg。在一些实施方案中，所述药物组合中吉西他滨的单位剂量为0.2g和/或1.0g。
在一些实施方案中，所述药物组合包括单位剂量为60-1800mg、100-1600mg、120-1600mg、180-1200mg、或240-600mg的抗TIM-3抗体或其抗原结合片段和单位剂量为10-500mg、50-500mg、50-200mg、或100-200mg的抗PD-1抗体或其抗原结合片段。在一些实施方案中，所述药物组合包括单位剂量为约60mg、约120mg、约160mg、约180mg、约200mg、约240mg、约280mg、约300mg、约320mg、约360mg、约400mg、约420mg、约440mg、约480mg、约520mg、约540mg、约560mg、约600mg、约640mg、约660mg、约680mg、约720mg、约760mg、约780mg、约800mg、约840mg、约880mg、约900mg、约920mg、约960mg、约1000mg、约1020mg、约1040mg、约1080mg、约1120mg、约1140mg、约1160mg、约1200mg、约1240mg、约1260mg、约1280mg、约1320mg、约1360mg、约1380mg、约1400mg、约1440mg、约1480mg、约1500mg、约1520mg、约1560mg、约1600mg、约1620mg、约1640mg、约1680mg、约1720mg、约1740mg、约1760mg、和/或约1800mg、或者上述任意值形成的范围的抗TIM-3抗体或其抗原结合片段，和单位剂量为约10mg、约20mg、约30mg、约40mg、约50mg、约60mg、约70mg、约80mg、约90mg、约100mg、约110mg、约120mg、约130mg、约140mg、约150mg、约160mg、约170mg、约180mg、约190mg、约200mg、约210mg、约220mg、约230mg、约240mg、约250mg、约260mg、约270mg、约280mg、约290mg、约300mg、约310mg、约320mg、约330mg、约340mg、约350mg、约360mg、约370mg、约380mg、约390mg、约400mg、约410mg、约420mg、约430mg、约440mg、约450mg、约460mg、约470mg、约480mg、约490mg、和/或约500mg、或者上述任意值形成的范围的抗PD-1抗体或其抗原结合片段。在一些实施方案中，所述药物组合包括单位剂量为约240mg、约300mg、约360mg和/或约600mg的抗TIM-3抗体或其抗原结合片段和单位剂量为约100mg和/或约200mg的抗PD-1抗体或其抗原结合片段。在一些实施方案中，所述药物组合包括单位剂量为约240mg和/或约600mg的抗TIM-3抗体或其抗原结合片段和单位剂量为约100mg的抗PD-1抗体或其抗原结合片段。
在一些实施方案中，所述药物组合还包括单位剂量为2.5mg、5mg、10mg、20mg、25mg、30mg、50mg和/或100mg的顺铂和单位剂量为0.2g和/或1.0g的吉西他滨。在一些实施方案中，所述药物组合还包括单位剂量为20mg、30mg和/或100mg的顺铂和单位剂量为0.2g和/或1.0g的吉西他滨。在一些实施方案中，所述药物组合还包括单位剂量为30mg的顺铂和单位剂量为0.2g和/或1.0g的吉西他滨。
在一些实施方案中，所述药物组合包括抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段、顺铂和吉西他滨。在一些具体的实施方案中，所述药物组合包括单位剂量为约240mg、约300mg、约360mg和/或约600mg的抗TIM-3抗体或其抗原结合片段，单位剂量为约100mg和/或约200mg的抗PD-1抗体或其抗原结合片段，单位剂量为2.5mg、5mg、10mg、20mg、25mg、30mg、50mg和/或100mg的顺铂，和单位剂量为0.2g和/或1.0g的吉西他滨。在一些具体的实施方案中，所述药物组合包括单位剂量为约240mg和/或约600mg的抗TIM-3抗体或其抗原结合片段，单位剂量为约100mg的抗PD-1抗体或其抗原结合片段，单位剂量为20mg、30mg和/或100mg的顺铂，和单位剂量为0.2g和/或1.0g的吉西他滨。在一些具体的实施方案中，所述药物组合包括单位剂量为约240mg和/或约600mg的抗TIM-3抗体或其抗原结合片段，单位剂量为约100mg的抗PD-1抗体或其抗原结合片段，单位剂量为30mg的顺铂，和单位剂量为0.2g和/或1.0g的吉西他滨。
在一些实施方案中，所述药物组合包括100-1800mg、600-1800mg、600-1500mg、或1200-1500mg的 抗TIM-3抗体或其抗原结合片段。在一些实施方案中，所述药物组合包括约100mg、约200mg、约300mg、约400mg、约500mg、约600mg、约700mg、约800mg、约900mg、约1000mg、约1100mg、约1200mg、约1300mg、约1400mg、约1500mg、约1600mg、约1700mg、或约1800mg、或上述任意值形成的范围的抗TIM-3抗体或其抗原结合片段。在一些实施方案中，所述药物组合包括约1200mg或约1500mg的抗TIM-3抗体或其抗原结合片段。在一些实施方案中，所述药物组合包括约1200mg的抗TIM-3抗体或其抗原结合片段。
在一些实施方案中，所述药物组合包括10-800mg、50-500mg、或100-200mg的抗PD-1抗体或其抗原结合片段。在一些实施方案中，所述药物组合包括约10mg、约50mg、约100mg、约120mg、约140mg、约160mg、约180mg、约200mg、约220mg、约240mg、约260mg、约280mg、约300mg、约350mg、约400mg、约450mg、约500mg、约550mg、约600mg、约650mg、约700mg、约750mg、或约800mg、或上述任意值形成的范围的抗PD-1抗体或其抗原结合片段。在一些实施方案中，所述药物组合包括约200mg的抗PD-1抗体或其抗原结合片段。
在一些实施方案中，所述药物组合还包括化疗药物。在一些实施方案中，所述化疗药物为顺铂和吉西他滨。在一些实施方案中，所述药物组合还包括40-80mg/m2、或40-75mg/m2的顺铂。在一些实施方案中，所述药物组合还包括40mg/m2、60mg/m2、75mg/m2、80mg/m2、或上述任意值形成的范围的顺铂。在一些实施方案中，所述药物组合还包括40mg/m2、60mg/m2或75mg/m2的顺铂。在一些实施方案中，所述药物组合还包括75mg/m2的顺铂。在一些实施方案中，所述药物组合还包括80mg/m2的顺铂。在一些实施方案中，所述药物组合还包括0.5-1.0g/m2的吉西他滨。在一些实施方案中，所述药物组合还包括0.5g/m2、0.75g/m2、1.0g/m2、或上述任意值形成的范围的吉西他滨。在一些实施方案中，所述药物组合还包括0.5g/m2、0.75g/m2或1.0g/m2的吉西他滨。在一些实施方案中，所述药物组合还包括1.0g/m2的吉西他滨。
在一些实施方案中，所述药物组合包括100-1800mg、600-1800mg、600-1500mg、或1200-1500mg的抗TIM-3抗体或其抗原结合片段，和10-800mg、50-500mg、或100-200mg的抗PD-1抗体或其抗原结合片段。在一些实施方案中，所述药物组合包括约100mg、约200mg、约300mg、约400mg、约500mg、约600mg、约700mg、约800mg、约900mg、约1000mg、约1100mg、约1200mg、约1300mg、约1400mg、约1500mg、约1600mg、约1700mg、或约1800mg、或上述任意值形成的范围的抗TIM-3抗体或其抗原结合片段，和约10mg、约50mg、约100mg、约120mg、约140mg、约160mg、约180mg、约200mg、约220mg、约240mg、约260mg、约280mg、约300mg、约350mg、约400mg、约450mg、约500mg、约550mg、约600mg、约650mg、约700mg、约750mg、或约800mg、或上述任意值形成的范围的抗PD-1抗体或其抗原结合片段。在一些实施方案中，所述药物组合包括约1200mg或约1500mg的抗TIM-3抗体或其抗原结合片段，和约200mg的抗PD-1抗体或其抗原结合片段。在一些实施方案中，所述药物组合包括约1200mg的抗TIM-3抗体或其抗原结合片段，和约200mg的抗PD-1抗体或其抗原结合片段。
在一些实施方案中，所述药物组合还包括40-80mg/m2、或40-75mg/m2的顺铂，和0.5-1.0g/m2的吉西他滨。在一些实施方案中，所述药物组合还包括40mg/m2、60mg/m2、75mg/m2、80mg/m2、或上述任意值形成的范围的顺铂，和0.5g/m2、0.75g/m2、1.0g/m2、或上述任意值形成的范围的吉西他滨。在一些实施方案中，所述药物组合还包括75mg/m2的顺铂、和1.0g/m2的吉西他滨。在一些实施方案中，所述药物组合还包括80mg/m2的顺铂、和1.0g/m2的吉西他滨。
在一些实施方案中，所述药物组合包括抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段、顺铂和吉西他滨。在一些具体的实施方案中，所述药物组合包括约1200mg或约1500mg的抗TIM-3抗体或其抗原结合片段，约200mg的抗PD-1抗体或其抗原结合片段，40mg/m2、60mg/m2、75mg/m2或80mg/m2的顺铂，和0.5g/m2、0.75g/m2或1.0g/m2的吉西他滨。在一些具体的实施方案中，所述药物组合包括约1200mg或约1500mg的抗TIM-3抗体或其抗原结合片段，约200mg的抗PD-1抗体或其抗原结合片段，75mg/m2的顺铂，和1.0g/m2的吉西他滨。在另一些具体的实施方案中，所述药物组合包括约1200mg或约1500mg的抗TIM-3抗体或其抗原结合片段，约200mg的抗PD-1抗体或其抗原结合片段，80mg/m2的顺铂，和1.0g/m2的吉西他滨。在一些具体的实施方案中，所述药物组合包括约1200mg的抗TIM-3抗体或其抗原结合片段，约200mg的抗PD-1抗体或其抗原结合片段，75mg/m2的顺铂，和 1.0g/m2的吉西他滨。
在一些实施方案中，所述药物组合中，抗TIM-3抗体或其抗原结合片段的含量为一日剂量。在一些实施方案中，所述药物组合中，抗TIM-3抗体或其抗原结合片段的含量为一日一次剂量。
在一些实施方案中，所述药物组合中，抗TIM-3抗体或其抗原结合片段的含量为统一剂量。
在一些实施方案中，所述药物组合中，抗TIM-3抗体或其抗原结合片段的含量为一个治疗周期的剂量，每个治疗周期为3周。
在一些实施方案中，所述药物组合中，抗PD-1抗体或其抗原结合片段的含量为一日剂量。在一些实施方案中，所述药物组合中，抗PD-1抗体或其抗原结合片段的含量为一日一次剂量。
在一些实施方案中，所述药物组合中，抗PD-1抗体或其抗原结合片段的含量为统一剂量。
在一些实施方案中，所述药物组合中，抗PD-1抗体或其抗原结合片段的含量为一个治疗周期的剂量，每个治疗周期为3周。在一些实施方案中，所述药物组合中，抗PD-1抗体或其抗原结合片段的含量为一个治疗周期的剂量，每个治疗周期为2周。
在一些实施方案中，所述药物组合中，顺铂的含量为一日剂量。在一些实施方案中，所述药物组合中，顺铂的含量为一日一次剂量。
在一些实施方案中，所述药物组合中，吉西他滨的含量为一日剂量。在一些实施方案中，所述药物组合中，吉西他滨的含量为一日一次剂量。
在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，其包括100-1800mg、600-1800mg、600-1500mg、或1200-1500mg的抗TIM-3抗体或其抗原结合片段。在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，其包括约100mg、约200mg、约300mg、约400mg、约500mg、约600mg、约700mg、约800mg、约900mg、约1000mg、约1100mg、约1200mg、约1300mg、约1400mg、约1500mg、约1600mg、约1700mg、或约1800mg、或上述任意值形成的范围的抗TIM-3抗体或其抗原结合片段。在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，其包括约1200mg或约1500mg的抗TIM-3抗体或其抗原结合片段。在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，其包括约1200mg的抗TIM-3抗体或其抗原结合片段。
在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，其包括10-800mg、50-500mg、或100-200mg的抗PD-1抗体或其抗原结合片段。在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，其包括约10mg、约50mg、约100mg、约120mg、约140mg、约160mg、约180mg、约200mg、约220mg、约240mg、约260mg、约280mg、约300mg、约350mg、约400mg、约450mg、约500mg、约550mg、约600mg、约650mg、约700mg、约750mg、或约800mg、或上述任意值形成的范围的抗PD-1抗体或其抗原结合片段。在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，其包括约200mg的抗PD-1抗体或其抗原结合片段。
在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，还包括化疗药物。在一些实施方案中，所述化疗药物为顺铂和吉西他滨。在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，还包括40-80mg/m2、或40-75mg/m2的顺铂。在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，还包括40mg/m2、60mg/m2、75mg/m2、80mg/m2、或上述任意值形成的范围的顺铂。在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，还包括40mg/m2、60mg/m2或75mg/m2的顺铂。在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，还包括75mg/m2的顺铂。在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，还包括80mg/m2的顺铂。在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，还包括1.0-2.0g/m2的吉西他滨。在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，还包括1.0g/m2、1.25g/m2、1.5g/m2、1.75g/m2、2.0g/m2、或上述任意值形成的范围的吉西他滨。在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，还包括1.0g/m2、1.25g/m2、1.5g/m2、1.75g/m2、2.0g/m2的吉西他滨。在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，还包括2.0g/m2的吉西他滨。
在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，其包括抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段。在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，其包括100-1800mg、600-1800mg、600-1500mg、或1200-1500mg的抗TIM-3抗体或其抗原结合片段， 和10-800mg、50-500mg、或100-200mg的抗PD-1抗体或其抗原结合片段。在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，其包括约100mg、约200mg、约300mg、约400mg、约500mg、约600mg、约700mg、约800mg、约900mg、约1000mg、约1100mg、约1200mg、约1300mg、约1400mg、约1500mg、约1600mg、约1700mg、或约1800mg、或上述任意值形成的范围的抗TIM-3抗体或其抗原结合片段，和约10mg、约50mg、约100mg、约120mg、约140mg、约160mg、约180mg、约200mg、约220mg、约240mg、约260mg、约280mg、约300mg、约350mg、约400mg、约450mg、约500mg、约550mg、约600mg、约650mg、约700mg、约750mg、或约800mg、或上述任意值形成的范围的抗PD-1抗体或其抗原结合片段。在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，其包括约1200mg或约1500mg的抗TIM-3抗体或其抗原结合片段，和约200mg的抗PD-1抗体或其抗原结合片段。在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，其包括约1200mg的抗TIM-3抗体或其抗原结合片段，和约200mg的抗PD-1抗体或其抗原结合片段。
在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，还包括40-80mg/m2、或40-75mg/m2的顺铂，和1.0-2.0g/m2的吉西他滨。在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，还包括40mg/m2、60mg/m2、75mg/m2、80mg/m2、或上述任意值形成的范围的顺铂，和1.0g/m2、1.25g/m2、1.5g/m2、1.75g/m2、2.0g/m2、或上述任意值形成的范围的吉西他滨。在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，还包括75mg/m2的顺铂、和2.0g/m2的吉西他滨。在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，还包括80mg/m2的顺铂、和2.0g/m2的吉西他滨。
在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，其包括抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段、顺铂和吉西他滨。在一些具体的实施方案中，所述药物组合适用于在单个治疗周期内施用，其包括约1200mg或约1500mg的抗TIM-3抗体或其抗原结合片段，约200mg的抗PD-1抗体或其抗原结合片段，40mg/m2、60mg/m2、75mg/m2或80mg/m2的顺铂，和1.0g/m2、1.25g/m2、1.5g/m2、1.75g/m2或2.0g/m2的吉西他滨。在一些具体的实施方案中，所述药物组合适用于在单个治疗周期内施用，其包括约1200mg或约1500mg的抗TIM-3抗体或其抗原结合片段，约200mg的抗PD-1抗体或其抗原结合片段，75mg/m2的顺铂，和2.0g/m2的吉西他滨。在另一些具体的实施方案中，所述药物组合适用于在单个治疗周期内施用，其包括约1200mg或约1500mg的抗TIM-3抗体或其抗原结合片段，约200mg的抗PD-1抗体或其抗原结合片段，80mg/m2的顺铂，和2.0g/m2的吉西他滨。在一些具体的实施方案中，所述药物组合适用于在单个治疗周期内施用，其包括约1200mg的抗TIM-3抗体或其抗原结合片段，约200mg的抗PD-1抗体或其抗原结合片段，75mg/m2的顺铂，和2.0g/m2的吉西他滨。
在一些实施方案中，本公开提供的联用药物组合包含：
(a)包括100-1800mg、600-1800mg、600-1500mg、或1200-1500mg的抗TIM-3抗体或其抗原结合片段，10-800mg、50-500mg、或100-200mg的抗PD-1抗体或其抗原结合片段，40-80mg/m2、40mg/m2、60mg/m2、75mg/m2或80mg/m2的顺铂，和1.0-2.0g/m2、1.0g/m2、1.25g/m2、1.5g/m2、1.75g/m2或2.0g/m2的吉西他滨的药物组合，其被制备为适合在第一治疗阶段的单个治疗周期向受试者给予；和
(b)包括100-1800mg、600-1800mg、600-1500mg、或1200-1500mg的抗TIM-3抗体或其抗原结合片段和10-800mg、50-500mg、或100-200mg的抗PD-1抗体或其抗原结合片段的药物组合，其被制备为适合在第二治疗阶段的单个治疗周期向受试者给予。
在一些实施方案中，本公开提供的联用药物组合包含：
(a)包括约1200mg或约1500mg的抗TIM-3抗体或其抗原结合片段，约200mg的抗PD-1抗体或其抗原结合片段，40mg/m2、60mg/m2、75mg/m2或80mg/m2的顺铂，和1.0g/m2、1.25g/m2、1.5g/m2、1.75g/m2或2.0g/m2的吉西他滨的药物组合，其被制备为适合在第一治疗阶段的单个治疗周期向受试者给予；和
(b)包括约1200mg或约1500mg的抗TIM-3抗体或其抗原结合片段和约200mg的抗PD-1抗体或其抗原结合片段的药物组合，其被制备为适合在第二治疗阶段的单个治疗周期向受试者给予。
在一些实施方案中，本公开提供的联用药物组合包含：
(a)包括约1200mg或约1500mg的抗TIM-3抗体或其抗原结合片段，约200mg的抗PD-1抗体或其抗原结合片段，75mg/m2的顺铂，和2.0g/m2的吉西他滨的药物组合，其被制备为适合在第一治疗阶段的 单个治疗周期向受试者给予；和
(b)包括约1200mg或约1500mg的抗TIM-3抗体或其抗原结合片段和约200mg的抗PD-1抗体或其抗原结合片段的药物组合，其被制备为适合在第二治疗阶段的单个治疗周期向受试者给予。
在一些实施方案中，本公开提供的联用药物组合包含：
(a)包括约1200mg或约1500mg的抗TIM-3抗体或其抗原结合片段，约200mg的抗PD-1抗体或其抗原结合片段，80mg/m2的顺铂，和2.0g/m2的吉西他滨的药物组合，其被制备为适合在第一治疗阶段的单个治疗周期向受试者给予；和
(b)包括约1200mg或约1500mg的抗TIM-3抗体或其抗原结合片段和约200mg的抗PD-1抗体或其抗原结合片段的药物组合，其被制备为适合在第二治疗阶段的单个治疗周期向受试者给予。
在一些实施方案中，本公开提供的联用药物组合包含：
(a)包括约1200mg的抗TIM-3抗体或其抗原结合片段，约200mg的抗PD-1抗体或其抗原结合片段，75mg/m2的顺铂，和2.0g/m2的吉西他滨的药物组合，其被制备为适合在第一治疗阶段的单个治疗周期向受试者给予；和
(b)包括约1200mg的抗TIM-3抗体或其抗原结合片段和约200mg的抗PD-1抗体或其抗原结合片段的药物组合，其被制备为适合在第二治疗阶段的单个治疗周期向受试者给予。
在一些实施方案中，所述第一治疗阶段的治疗周期包括1-14个治疗周期，优选2-12个治疗周期、2-10个治疗周期，更优选2-8个治疗周期，例如：2-8个治疗周期，3-8个治疗周期，4-8个治疗周期，2-7个治疗周期，3-7个治疗周期，4-7个治疗周期，2-6个治疗周期，3-6个治疗周期，或4-6个治疗周期；最优选4-6个治疗周期，例如：4个治疗周期，5个治疗周期，和/或6个治疗周期。
在一些实施方案中，所述第二治疗阶段在第一治疗阶段之后。在一些实施方案中，所述第二治疗阶段是从第一治疗阶段结束后持续直到失去临床获益、毒性不可耐受、疗效评价为PD、和/或研究者认为不适合继续用药。
在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段可以是含抗TIM-3抗体或其抗原结合片段的药物组合物。其中，含抗TIM-3抗体或其抗原结合片段的药物组合物为单剂量或多剂量，优选为多剂量。在一些实施方案中，所述多剂量可以由单剂量为含约240mg、约300mg、约360mg和/或约600mg抗TIM-3抗体或其抗原结合片段的药物组合物组成。在一些实施方案中，所述多剂量可以由单剂量为含约240mg和/或约600mg抗TIM-3抗体或其抗原结合片段的药物组合物组成。
在一些实施方案中，所述抗PD-1抗体或其抗原结合片段可以是含抗PD-1抗体或其抗原结合片段的药物组合物。其中，含抗PD-1抗体或其抗原结合片段的药物组合物为单剂量或多剂量，优选为多剂量。在一些实施方案中，所述多剂量可以由单剂量为含约100mg和/或约200mg抗PD-1抗体或其抗原结合片段的药物组合物组成。在一些实施方案中，所述多剂量可以由单剂量为含约100mg抗PD-1抗体或其抗原结合片段的药物组合物组成。
在一些实施方案中，所述化疗药物可以是含化疗药物的药物组合物。其中，含化疗药物的药物组合物为单剂量或多剂量，优选为多剂量。在一些实施方案中，所述化疗药物为顺铂和吉西他滨。在一些实施方案中，所述顺铂可以是含顺铂的药物组合物。其中，含顺铂的药物组合物为单剂量或多剂量，优选为多剂量。在一些实施方案中，所述多剂量可以由单剂量为含2.5mg、5mg、10mg、20mg、25mg、30mg、50mg和/或100mg顺铂的药物组合物组成。在一些实施方案中，所述多剂量可以由单剂量为含30mg顺铂的药物组合物组成。在一些实施方案中，所述吉西他滨可以是含吉西他滨的药物组合物。其中，含吉西他滨的药物组合物为单剂量或多剂量，优选为多剂量。在一些实施方案中，所述多剂量可以由单剂量为含0.2g和/或1.0g吉西他滨的药物组合物组成。
在一些实施方案中，所述药物组合中，所述抗TIM-3抗体或其抗原结合片段:抗PD-1抗体或其抗原结合片段的质量比为(0.1-180):1、(0.2-50):1、(0.5-9):1、(3-7.5):1、(4-7.5):1或(6-7.5):1；其中，抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段可分开包装或包装在一起。并且其中，抗TIM-3抗体或其抗原结合片段能够以单份或多份进行包装，抗PD-1抗体或其抗原结合片段能够以单份或多份进行包装。在一些实施方案中，抗TIM-3抗体或其抗原结合片段能够以单份或多个等份(例如2等份、3等份、4等份、5等份、6等份、7等份、8等份或更多等份)进行包装，抗PD-1抗体或其抗原结合片段能够以单 份或多个等份(例如2等份或其他等份)进行包装。
在一些实施方案中，所述药物组合包括含抗TIM-3抗体或其抗原结合片段的药物组合物和含抗PD-1抗体或其抗原结合片段的药物组合物，其中含抗TIM-3抗体或其抗原结合片段的药物组合物被制备为适合向患者给予100-1800mg、600-1800mg、600-1500mg、或1200-1500mg抗TIM-3抗体或其抗原结合片段的单剂量或多剂量，含抗PD-1抗体或其抗原结合片段的药物组合物被制备为适合向患者给予10-800mg、50-500mg、或100-200mg抗PD-1抗体或其抗原结合片段的单剂量或多剂量。在一些实施方案中，所述药物组合包括含抗TIM-3抗体或其抗原结合片段的药物组合物和含抗PD-1抗体或其抗原结合片段的药物组合物，其中含抗TIM-3抗体或其抗原结合片段的药物组合物被制备为适合向患者给予约100mg、约200mg、约300mg、约400mg、约500mg、约600mg、约700mg、约800mg、约900mg、约1000mg、约1100mg、约1200mg、约1300mg、约1400mg、约1500mg、约1600mg、约1700mg、或约1800mg、或上述任意值形成的范围的抗TIM-3抗体或其抗原结合片段的单剂量或多剂量，含抗PD-1抗体或其抗原结合片段的药物组合物被制备为适合向患者给予约10mg、约50mg、约100mg、约120mg、约140mg、约160mg、约180mg、约200mg、约220mg、约240mg、约260mg、约280mg、约300mg、约350mg、约400mg、约450mg、约500mg、约550mg、约600mg、约650mg、约700mg、约750mg、或约800mg、或上述任意值形成的范围的抗PD-1抗体或其抗原结合片段的单剂量或多剂量。在一些实施方案中，所述药物组合包括含抗TIM-3抗体或其抗原结合片段的药物组合物和含抗PD-1抗体或其抗原结合片段的药物组合物，其中含抗TIM-3抗体或其抗原结合片段的药物组合物被制备为适合向患者给予约1200mg或约1500mg抗TIM-3抗体或其抗原结合片段的单剂量或多剂量，含抗PD-1抗体或其抗原结合片段的药物组合物被制备为适合向患者给予约200mg抗PD-1抗体或其抗原结合片段的单剂量或多剂量。在一些实施方案中，所述药物组合包括含抗TIM-3抗体或其抗原结合片段的药物组合物和含抗PD-1抗体或其抗原结合片段的药物组合物，其中含抗TIM-3抗体或其抗原结合片段的药物组合物被制备为适合向患者给予约1200mg抗TIM-3抗体或其抗原结合片段的单剂量或多剂量，含抗PD-1抗体或其抗原结合片段的药物组合物被制备为适合向患者给予约200mg抗PD-1抗体或其抗原结合片段的单剂量或多剂量。
在一些实施方案中，所述药物组合还包括化疗药物。在一些实施方案中，所述化疗药物为顺铂和吉西他滨。在一些实施方案中，所述药物组合还包括含顺铂的药物组合物和含吉西他滨的药物组合物，其中含顺铂的药物组合物被制备为适合向患者给予40-80mg/m2、或40-75mg/m2顺铂的单剂量或多剂量，含吉西他滨的药物组合物被制备为适合向患者给予0.5-1.0g/m2吉西他滨的单剂量或多剂量。在一些实施方案中，所述药物组合还包括含顺铂的药物组合物和含吉西他滨的药物组合物，其中含顺铂的药物组合物被制备为适合向患者给予40mg/m2、60mg/m2、75mg/m2、80mg/m2、或上述任意值形成的范围的顺铂的单剂量或多剂量，含吉西他滨的药物组合物被制备为适合向患者给予0.5g/m2、0.75g/m2、1.0g/m2、或上述任意值形成的范围的吉西他滨的单剂量或多剂量。在一些实施方案中，所述药物组合还包括含顺铂的药物组合物和含吉西他滨的药物组合物，其中含顺铂的药物组合物被制备为适合向患者给予75mg/m2顺铂的单剂量或多剂量，含吉西他滨的药物组合物被制备为适合向患者给予1.0g/m2吉西他滨的单剂量或多剂量。在一些实施方案中，所述药物组合还包括含顺铂的药物组合物和含吉西他滨的药物组合物，其中含顺铂的药物组合物被制备为适合向患者给予80mg/m2顺铂的单剂量或多剂量，含吉西他滨的药物组合物被制备为适合向患者给予1.0g/m2吉西他滨的单剂量或多剂量。
在一些实施方案中，所述药物组合包括含抗TIM-3抗体或其抗原结合片段的药物组合物、含抗PD-1抗体或其抗原结合片段的药物组合物、含顺铂的药物组合物、和含吉西他滨的药物组合物。在一些具体的实施方案中，所述药物组合中，含抗TIM-3抗体或其抗原结合片段的药物组合物被制备为适合向患者给予约1200mg或约1500mg抗TIM-3抗体或其抗原结合片段的单剂量或多剂量，含抗PD-1抗体或其抗原结合片段的药物组合物被制备为适合向患者给予约200mg抗PD-1抗体或其抗原结合片段的单剂量或多剂量，含顺铂的药物组合物被制备为适合向患者给予40mg/m2、60mg/m2、75mg/m2或80mg/m2顺铂的单剂量或多剂量，含吉西他滨的药物组合物被制备为适合向患者给予0.5g/m2、0.75g/m2或1.0g/m2吉西他滨的单剂量或多剂量。在一些具体的实施方案中，所述药物组合中，含抗TIM-3抗体或其抗原结合片段的药物组合物被制备为适合向患者给予约1200mg或约1500mg抗TIM-3抗体或其抗原结合片段的单剂量或多剂量，含抗PD-1抗体或其抗原结合片段的药物组合物被制备为适合向患者给予约200mg抗PD-1抗 体或其抗原结合片段的单剂量或多剂量，含顺铂的药物组合物被制备为适合向患者给予75mg/m2顺铂的单剂量或多剂量，含吉西他滨的药物组合物被制备为适合向患者给予1.0g/m2吉西他滨的单剂量或多剂量。在一些具体的实施方案中，所述药物组合中，含抗TIM-3抗体或其抗原结合片段的药物组合物被制备为适合向患者给予约1200mg或约1500mg抗TIM-3抗体或其抗原结合片段的单剂量或多剂量，含抗PD-1抗体或其抗原结合片段的药物组合物被制备为适合向患者给予约200mg抗PD-1抗体或其抗原结合片段的单剂量或多剂量，含顺铂的药物组合物被制备为适合向患者给予80mg/m2顺铂的单剂量或多剂量，含吉西他滨的药物组合物被制备为适合向患者给予1.0g/m2吉西他滨的单剂量或多剂量。在一些具体的实施方案中，所述药物组合中，含抗TIM-3抗体或其抗原结合片段的药物组合物被制备为适合向患者给予约1200mg抗TIM-3抗体或其抗原结合片段的单剂量或多剂量，含抗PD-1抗体或其抗原结合片段的药物组合物被制备为适合向患者给予约200mg抗PD-1抗体或其抗原结合片段的单剂量或多剂量，含顺铂的药物组合物被制备为适合向患者给予75mg/m2顺铂的单剂量或多剂量，含吉西他滨的药物组合物被制备为适合向患者给予1.0g/m2吉西他滨的单剂量或多剂量。
在一些实施方案中，所述药物组合包括含抗TIM-3抗体或其抗原结合片段的药物组合物和含抗PD-1抗体或其抗原结合片段的药物组合物，其中含抗TIM-3抗体或其抗原结合片段的药物组合物被制备为适合第一次给药时向患者给予100-1800mg、600-1800mg、600-1500mg、或1200-1500mg抗TIM-3抗体或其抗原结合片段的单剂量或多剂量，含抗PD-1抗体或其抗原结合片段的药物组合物被制备为适合第一次给药时向患者给予10-800mg、50-500mg、或100-200mg抗PD-1抗体或其抗原结合片段的单剂量或多剂量。在一些实施方案中，所述药物组合包括含抗TIM-3抗体或其抗原结合片段的药物组合物和含抗PD-1抗体或其抗原结合片段的药物组合物，其中含抗TIM-3抗体或其抗原结合片段的药物组合物被制备为适合第一次给药时向患者给予约100mg、约200mg、约300mg、约400mg、约500mg、约600mg、约700mg、约800mg、约900mg、约1000mg、约1100mg、约1200mg、约1300mg、约1400mg、约1500mg、约1600mg、约1700mg、或约1800mg、或上述任意值形成的范围的抗TIM-3抗体或其抗原结合片段的单剂量或多剂量，含抗PD-1抗体或其抗原结合片段的药物组合物被制备为适合第一次给药时向患者给予约10mg、约50mg、约100mg、约120mg、约140mg、约160mg、约180mg、约200mg、约220mg、约240mg、约260mg、约280mg、约300mg、约350mg、约400mg、约450mg、约500mg、约550mg、约600mg、约650mg、约700mg、约750mg、或约800mg、或上述任意值形成的范围的抗PD-1抗体或其抗原结合片段的单剂量或多剂量。在一些实施方案中，所述药物组合包括含抗TIM-3抗体或其抗原结合片段的药物组合物和含抗PD-1抗体或其抗原结合片段的药物组合物，其中含抗TIM-3抗体或其抗原结合片段的药物组合物被制备为适合第一次给药时向患者给予约1200mg或约1500mg抗TIM-3抗体或其抗原结合片段的单剂量或多剂量，含抗PD-1抗体或其抗原结合片段的药物组合物被制备为适合第一次给药时向患者给予约200mg抗PD-1抗体或其抗原结合片段的单剂量或多剂量。在一些实施方案中，所述药物组合包括含抗TIM-3抗体或其抗原结合片段的药物组合物和含抗PD-1抗体或其抗原结合片段的药物组合物，其中含抗TIM-3抗体或其抗原结合片段的药物组合物被制备为适合第一次给药时向患者给予约1200mg抗TIM-3抗体或其抗原结合片段的单剂量或多剂量，含抗PD-1抗体或其抗原结合片段的药物组合物被制备为适合第一次给药时向患者给予约200mg抗PD-1抗体或其抗原结合片段的单剂量或多剂量。
在一些实施方案中，所述药物组合还包括化疗药物。在一些实施方案中，所述化疗药物为顺铂和吉西他滨。在一些实施方案中，所述药物组合还包括含顺铂的药物组合物和含吉西他滨的药物组合物，其中含顺铂的药物组合物被制备为适合第一次给药时向患者给予40-80mg/m2、或40-75mg/m2顺铂的单剂量或多剂量，含吉西他滨的药物组合物被制备为适合连续两周、每周向患者给予0.5-1.0g/m2吉西他滨的单剂量或多剂量。在一些实施方案中，所述药物组合还包括含顺铂的药物组合物和含吉西他滨的药物组合物，其中含顺铂的药物组合物被制备为适合第一次给药时向患者给予40mg/m2、60mg/m2、75mg/m2、80mg/m2、或上述任意值形成的范围的顺铂的单剂量或多剂量，含吉西他滨的药物组合物被制备为适合连续两周、每周向患者给予0.5g/m2、0.75g/m2、1.0g/m2、或上述任意值形成的范围的吉西他滨的单剂量或多剂量。在一些实施方案中，所述药物组合还包括含顺铂的药物组合物和含吉西他滨的药物组合物，其中含顺铂的药物组合物被制备为适合第一次给药时向患者给予75mg/m2顺铂的单剂量或多剂量，含吉西他滨的药物组合物被制备为适合连续两周、每周向患者给予1.0g/m2吉西他滨的单剂量或多剂量。在一些实施方案中， 所述药物组合还包括含顺铂的药物组合物和含吉西他滨的药物组合物，其中含顺铂的药物组合物被制备为适合第一次给药时向患者给予80mg/m2顺铂的单剂量或多剂量，含吉西他滨的药物组合物被制备为适合连续两周、每周向患者给予1.0g/m2吉西他滨的单剂量或多剂量。
在一些实施方案中，所述药物组合包括含抗TIM-3抗体或其抗原结合片段的药物组合物、含抗PD-1抗体或其抗原结合片段的药物组合物、含顺铂的药物组合物、和含吉西他滨的药物组合物。在一些具体的实施方案中，所述药物组合中，含抗TIM-3抗体或其抗原结合片段的药物组合物被制备为适合第一次给药时向患者给予约1200mg或约1500mg抗TIM-3抗体或其抗原结合片段的单剂量或多剂量，含抗PD-1抗体或其抗原结合片段的药物组合物被制备为适合第一次给药时向患者给予约200mg抗PD-1抗体或其抗原结合片段的单剂量或多剂量，含顺铂的药物组合物被制备为适合第一次给药时向患者给予40mg/m2、60mg/m2、75mg/m2或80mg/m2顺铂的单剂量或多剂量，含吉西他滨的药物组合物被制备为适合连续两周、每周向患者给予0.5g/m2、0.75g/m2或1.0g/m2吉西他滨的单剂量或多剂量。在一些具体的实施方案中，所述药物组合中，含抗TIM-3抗体或其抗原结合片段的药物组合物被制备为适合第一次给药时向患者给予约1200mg或约1500mg抗TIM-3抗体或其抗原结合片段的单剂量或多剂量，含抗PD-1抗体或其抗原结合片段的药物组合物被制备为适合第一次给药时向患者给予约200mg抗PD-1抗体或其抗原结合片段的单剂量或多剂量，含顺铂的药物组合物被制备为适合第一次给药时向患者给予75mg/m2顺铂的单剂量或多剂量，含吉西他滨的药物组合物被制备为适合连续两周、每周向患者给予1.0g/m2吉西他滨的单剂量或多剂量。在一些具体的实施方案中，所述药物组合中，含抗TIM-3抗体或其抗原结合片段的药物组合物被制备为适合第一次给药时向患者给予约1200mg或约1500mg抗TIM-3抗体或其抗原结合片段的单剂量或多剂量，含抗PD-1抗体或其抗原结合片段的药物组合物被制备为适合第一次给药时向患者给予约200mg抗PD-1抗体或其抗原结合片段的单剂量或多剂量，含顺铂的药物组合物被制备为适合第一次给药时向患者给予80mg/m2顺铂的单剂量或多剂量，含吉西他滨的药物组合物被制备为适合连续两周、每周向患者给予1.0g/m2吉西他滨的单剂量或多剂量。在一些具体的实施方案中，所述药物组合中，含抗TIM-3抗体或其抗原结合片段的药物组合物被制备为适合第一次给药时向患者给予约1200mg抗TIM-3抗体或其抗原结合片段的单剂量或多剂量，含抗PD-1抗体或其抗原结合片段的药物组合物被制备为适合第一次给药时向患者给予约200mg抗PD-1抗体或其抗原结合片段的单剂量或多剂量，含顺铂的药物组合物被制备为适合第一次给药时向患者给予75mg/m2顺铂的单剂量或多剂量，含吉西他滨的药物组合物被制备为适合连续两周、每周向患者给予1.0g/m2吉西他滨的单剂量或多剂量。
在另一方面，本公开提供用于治疗肿瘤的试剂盒，所述试剂盒包括含抗TIM-3抗体或其抗原结合片段的药物组合物和含抗PD-1抗体或其抗原结合片段的药物组合物，以及将含抗TIM-3抗体或其抗原结合片段的药物组合物和含抗PD-1抗体或其抗原结合片段的药物组合物联合使用以治疗肿瘤的说明。
在另一些实施方案中，所述试剂盒包括含抗TIM-3抗体或其抗原结合片段的药物组合物、含抗PD-1抗体或其抗原结合片段的药物组合物和含化疗药物的药物组合物，以及将含抗TIM-3抗体或其抗原结合片段的药物组合物、含抗PD-1抗体或其抗原结合片段的药物组合物和含化疗药物的药物组合物联合使用以治疗肿瘤的说明。在一些实施方案中，所述化疗药物为铂类抗肿瘤药物和/或抗代谢类抗肿瘤药物。在一些实施方案中，所述化疗药物为铂类抗肿瘤药物和/或胞嘧啶类抗肿瘤药物。在一些实施方案中，所述化疗药物为顺铂和吉西他滨。在一些具体的实施方案中，所述试剂盒包括含抗TIM-3抗体或其抗原结合片段的药物组合物、含抗PD-1抗体或其抗原结合片段的药物组合物、含顺铂的药物组合物和含吉西他滨的药物组合物，以及将含抗TIM-3抗体或其抗原结合片段的药物组合物、含抗PD-1抗体或其抗原结合片段的药物组合物、含顺铂的药物组合物和含吉西他滨的药物组合物联合使用以治疗肿瘤的说明。
在另一方面，本公开提供用于治疗肿瘤的试剂盒，所述试剂盒包括含抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段的药物组合物，以及使用含抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段的药物组合物治疗肿瘤的说明。
在另一些实施方案中，所述试剂盒包括含抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段的药物组合物、和含化疗药物的药物组合物，以及将含抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段的药物组合物、和含化疗药物的药物组合物联合使用以治疗肿瘤的说明。在一些实施方案中，所述化疗药物为铂类抗肿瘤药物和/或抗代谢类抗肿瘤药物。在一些实施方案中，所述化疗药物 为铂类抗肿瘤药物和/或胞嘧啶类抗肿瘤药物。在一些实施方案中，所述化疗药物为顺铂和吉西他滨。在一些具体的实施方案中，所述试剂盒包括含抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段的药物组合物、含顺铂的药物组合物和含吉西他滨的药物组合物，以及将含抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段的药物组合物、含顺铂的药物组合物和含吉西他滨的药物组合物联合使用以治疗肿瘤的说明。
在另一方面，本公开还提供用于治疗肿瘤的药物包，其在独立的容器中分别包含单包装的药物组合物，其中，在第一个容器中包括含抗TIM-3抗体或其抗原结合片段的药物组合物，在第二个容器中包括含抗PD-1抗体或其抗原结合片段的药物组合物；任选地，还包含一个或多个其他容器，在其他容器中包括含化疗药物的药物组合物。在一些实施方案中，所述化疗药物为铂类抗肿瘤药物和/或抗代谢类抗肿瘤药物。在一些实施方案中，所述化疗药物为铂类抗肿瘤药物和/或胞嘧啶类抗肿瘤药物。在一些实施方案中，所述化疗药物为顺铂和吉西他滨。在一些具体实施方案中，所述药物包在独立的容器中分别包含单包装的药物组合物，其中，在第一个容器中包括含抗TIM-3抗体或其抗原结合片段的药物组合物，并在第二个容器中包括含抗PD-1抗体或其抗原结合片段的药物组合物。在一些具体实施方案中，所述药物包在独立的容器中分别包含单包装的药物组合物，其中，在第一个容器中包括含抗TIM-3抗体或其抗原结合片段的药物组合物，在第二个容器中包括含抗PD-1抗体或其抗原结合片段的药物组合物，在第三个容器中包括含顺铂的药物组合物，并在第四个容器中包括含吉西他滨的药物组合物。
在另一方面，本公开还提供用于治疗肿瘤的药物包，其在独立的容器中分别包含单包装的药物组合物，其中，在第一个容器中包括含抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段的药物组合物；任选地，还包含一个或多个其他容器，在其他容器中包括含化疗药物的药物组合物。在一些实施方案中，所述化疗药物为铂类抗肿瘤药物和/或抗代谢类抗肿瘤药物。在一些实施方案中，所述化疗药物为铂类抗肿瘤药物和/或胞嘧啶类抗肿瘤药物。在一些实施方案中，所述化疗药物为顺铂和吉西他滨。在一些具体实施方案中，所述药物包在独立的容器中分别包含单包装的药物组合物，其中，在第一个容器中包括含抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段的药物组合物。在一些具体实施方案中，所述药物包在独立的容器中分别包含单包装的药物组合物，其中，在第一个容器中包括含抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段的药物组合物，在第二个容器中包括含顺铂的药物组合物，并在第三个容器中包括含吉西他滨的药物组合物。
在一些具体实施方案中，所述试剂盒或药物包中，含抗TIM-3抗体或其抗原结合片段的药物组合物为液体药物组合物或固体药物组合物。在一些具体实施方案中，所述含抗TIM-3抗体或其抗原结合片段的药物组合物为注射液。在一些具体实施方案中，所述含抗TIM-3抗体或其抗原结合片段的药物组合物为冻干制剂。
在一些具体实施方案中，所述试剂盒或药物包中，含抗PD-1抗体或其抗原结合片段的药物组合物为液体药物组合物或固体药物组合物。在一些具体实施方案中，所述含抗PD-1抗体或其抗原结合片段的药物组合物为注射液。在一些具体实施方案中，所述含抗PD-1抗体或其抗原结合片段的药物组合物为冻干制剂。
在一些具体实施方案中，所述试剂盒或药物包中，含抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段的药物组合物为液体药物组合物或固体药物组合物。在一些具体实施方案中，所述含抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段的药物组合物为注射液。在一些具体实施方案中，所述含抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段的药物组合物为冻干制剂。在一些具体实施方案中，所述试剂盒或药物包中，含化疗药物的药物组合物为液体药物组合物或固体药物组合物。在一些具体实施方案中，所述试剂盒或药物包中，含顺铂的药物组合物为液体药物组合物或固体药物组合物。在一些具体实施方案中，所述试剂盒或药物包中，含吉西他滨的药物组合物为液体药物组合物或固体药物组合物。在一些具体实施方案中，所述含顺铂的药物组合物为注射液。在一些具体实施方案中，所述含吉西他滨的药物组合物为注射液。在一些具体实施方案中，所述含顺铂的药物组合物为粉剂。在一些具体实施方案中，所述含吉西他滨的药物组合物为粉剂。
在一些实施方案中，所述肿瘤为实体瘤。在一些实施方案中，所述实体瘤为鼻咽癌。
药物组合的用途
本公开还提供在受试者中治疗肿瘤的方法，其包括向受试者给予有效量的本公开的药物组合。另外，本公开还提供了本公开的药物组合一线治疗受试者中肿瘤的用途。
在另一方面，本公开还提供本公开的药物组合在制备用于治疗受试者中肿瘤的药物中的用途。另外，本公开还提供了本公开的药物组合在制备用于一线治疗受试者中肿瘤的药物中的用途。
在一些实施方案中，在所述方法或用途中，所述药物组合包括抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段。
在一些实施方案中，在所述方法或用途中，所述药物组合包括抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段和化疗药物。在一些实施方案中，所述化疗药物包括但不限于铂类抗肿瘤药物、紫杉烷类抗肿瘤药物、抗代谢类抗肿瘤药物、喜树碱类抗肿瘤药物、氮芥类抗肿瘤药物、蒽环类抗肿瘤药物、长春碱类抗肿瘤药物、鬼臼生物碱类抗肿瘤药物、和激素类抗肿瘤药物中一种或多种。在一些实施方案中，所述化疗药物为铂类抗肿瘤药物和/或抗代谢类抗肿瘤药物。在一些实施方案中，所述化疗药物为铂类抗肿瘤药物和/或胞嘧啶类抗肿瘤药物。在一些具体实施方案中，所述化疗药物为顺铂和吉西他滨。在一些实施方案中，在所述方法或用途中，所述药物组合包括抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段、铂类抗肿瘤药物和抗代谢类抗肿瘤药物。在一些实施方案中，在所述方法或用途中，所述药物组合包括抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段、铂类抗肿瘤药物和胞嘧啶类抗肿瘤药物。在一些实施方案中，在所述方法或用途中，所述药物组合包括抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段、顺铂和吉西他滨。
本公开还提供抗TIM-3抗体或其抗原结合片段在制备用于治疗受试者的肿瘤的药物中的用途，其中所述药物用于与本公开的抗PD-1抗体抗原结合片段联合使用。
本公开还提供抗TIM-3抗体或其抗原结合片段在制备用于治疗受试者的肿瘤的药物中的用途，其中所述药物用于与本公开的抗PD-1抗体抗原结合片段和化疗药物联合使用。
本公开还提供抗TIM-3抗体或其抗原结合片段和抗PD-1抗体抗原结合片段在制备用于治疗受试者的肿瘤的药物中的用途，其中所述药物用于与化疗药物联合使用。
在一些实施方案中，所述化疗药物包括但不限于铂类抗肿瘤药物、紫杉烷类抗肿瘤药物、抗代谢类抗肿瘤药物、喜树碱类抗肿瘤药物、氮芥类抗肿瘤药物、蒽环类抗肿瘤药物、长春碱类抗肿瘤药物、鬼臼生物碱类抗肿瘤药物、和激素类抗肿瘤药物中一种或多种。在一些实施方案中，所述化疗药物为铂类抗肿瘤药物和/或抗代谢类抗肿瘤药物。在一些实施方案中，所述化疗药物为铂类抗肿瘤药物和/或胞嘧啶类抗肿瘤药物。在一些具体实施方案中，所述化疗药物为顺铂和吉西他滨。在一些实施方案中，本公开提供了抗TIM-3抗体或其抗原结合片段在制备用于治疗受试者的肿瘤的药物中的用途，其中所述药物用于与本公开的抗PD-1抗体抗原结合片段、顺铂和吉西他滨联合使用。在一些实施方案中，本公开提供了抗TIM-3抗体或其抗原结合片段和抗PD-1抗体抗原结合片段在制备用于治疗受试者的肿瘤的药物中的用途，其中所述药物用于与顺铂和吉西他滨联合使用。
在一些实施方案中，在所述方法或用途中，其包括在第一治疗阶段向受试者给予有效量的本公开的药物组合，并且在第二治疗阶段向受试者给予有效量的本公开的药物组合。
在一些实施方案中，在所述方法或用途中，其包括在第一治疗阶段向受试者给予有效量的包括抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段和化疗药物的药物组合；并且
在第二治疗阶段向受试者给予有效量的包括抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段的药物组合。
在一些实施方案中，在所述方法或用途中，其包括在第一治疗阶段向受试者给予有效量的包括抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段、铂类抗肿瘤药物和抗代谢类抗肿瘤药物的药物组合；并且
在第二治疗阶段向受试者给予有效量的包括抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段的药物组合。
在一些实施方案中，在所述方法或用途中，其包括在第一治疗阶段向受试者给予有效量的包括抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段、铂类抗肿瘤药物和胞嘧啶类抗肿瘤药物的药物组合；并且
在第二治疗阶段向受试者给予有效量的包括抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段的药物组合。
在一些实施方案中，在所述方法或用途中，其包括在第一治疗阶段向受试者给予有效量的包括抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段、顺铂和吉西他滨的药物组合；并且
在第二治疗阶段向受试者给予有效量的包括抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段的药物组合。
在一些实施方案中，所述第一治疗阶段的治疗周期包括1-14个治疗周期，优选2-12个治疗周期、2-10个治疗周期，更优选2-8个治疗周期，例如：2-8个治疗周期，3-8个治疗周期，4-8个治疗周期，2-7个治疗周期，3-7个治疗周期，4-7个治疗周期，2-6个治疗周期，3-6个治疗周期，或4-6个治疗周期；最优选4-6个治疗周期，例如：4个治疗周期，5个治疗周期，和/或6个治疗周期。
在一些实施方案中，所述第二治疗阶段在第一治疗阶段之后。在一些实施方案中，所述第二治疗阶段是从第一治疗阶段结束后持续直到失去临床获益、毒性不可耐受、疗效评价为PD、研究者认为不适合继续用药。
在一些实施方案中，在所述方法或用途中，所述抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段，可同时、先后和/或交替给药。在一些实施方案中，在所述方法或用途中，所述抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段先后给药。在一些实施方案中，在所述方法或用途中，所述抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段同时给药。在一些实施方案中，在所述方法或用途中，所述抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段各自呈药物组合物的形式，可同时、先后和/或交替给药。在一些实施方案中，在所述方法或用途中，所述抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段各自呈药物组合物的形式，先后给药。在一些实施方案中，在所述方法或用途中，先施用抗PD-1抗体或其抗原结合片段，再施用抗TIM-3抗体或其抗原结合片段。在一些实施方案中，在所述方法或用途中，所述抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段各自呈药物组合物的形式，先施用含抗PD-1抗体或其抗原结合片段的药物组合物，再施用含抗TIM-3抗体或其抗原结合片段的药物组合物。在一些实施方案中，在所述方法或用途中，所述抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段配制在单一制剂中，同时给药。
在一些实施方案中，在所述方法或用途中，所述抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段、和化疗药物，可同时、先后和/或交替给药。在一些实施方案中，在所述方法或用途中，所述抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段、和化疗药物各自呈药物组合物的形式，可同时、先后和/或交替给药。在一些实施方案中，在所述方法或用途中，所述抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段、顺铂和吉西他滨，可同时、先后和/或交替给药。在一些实施方案中，在所述方法或用途中，所述抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段、顺铂和吉西他滨各自呈药物组合物的形式，可同时、先后和/或交替给药。在一些实施方案中，在所述方法或用途中，所述抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段配制在单一制剂中，所述单一制剂和化疗药物，可同时、先后和/或交替给药。在一些实施方案中，在所述方法或用途中，所述抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段配制在单一制剂中，所述单一制剂、顺铂和吉西他滨，可同时、先后和/或交替给药。在一些实施方案中，在所述方法或用途中，所述抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段配制在单一制剂中，所述单一制剂和含化疗药物的药物组合物，可同时、先后和/或交替给药。在一些实施方案中，在所述方法或用途中，所述抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段配制在单一制剂中，所述单一制剂、含顺铂的药物组合物和含吉西他滨的药物组合物，可同时、先后和/或交替给药。
在一些实施方案中，在所述方法或用途中，所述抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段分别以相同或不同的给药方案进行给药。在一些实施方案中，在所述方法或用途中，所述抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段分别以不同的给药方案进行给药。
在一些实施方案中，在所述方法或用途中，所述抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段和化疗药物分别以相同或不同的给药方案进行给药。在一些实施方案中，在所述方法或用途中，所述抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段、顺铂和吉西他滨分别以相同 或不同的给药方案进行给药。在一些具体的实施方案中，在所述方法或用途中，所述抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段和顺铂和吉西他滨分别以不同的给药方案进行给药。
在一些实施方案中，在所述方法或用途中，所述抗TIM-3抗体或其抗原结合片段每周(q1w)、每2周(q2w)、每3周(q3w)、或每4周(q4w)施用一次。在一个具体的实施方案中，每3周给予抗TIM-3抗体或其抗原结合片段一次。在一个具体的实施方案中，每4周给予抗TIM-3抗体或其抗原结合片段一次。在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段每次以100-1800mg、600-1800mg、600-1500mg、或1200-1500mg的剂量施用。在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段每次以约100mg、约200mg、约300mg、约400mg、约500mg、约600mg、约700mg、约800mg、约900mg、约1000mg、约1100mg、约1200mg、约1300mg、约1400mg、约1500mg、约1600mg、约1700mg、或约1800mg、或上述任意值形成的范围的剂量施用。在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段每次以约1200mg或约1500mg的剂量施用。在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段每1周、每2周、每3周、或每4周施用一次，每次以1200-1500mg抗TIM-3抗体或其抗原结合片段的剂量施用。在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段每1周、每2周、每3周、或每4周施用一次，每次以约1200mg或约1500mg抗TIM-3抗体或其抗原结合片段的剂量施用。在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段每3周施用一次，每次以约1200mg或约1500mg抗TIM-3抗体或其抗原结合片段的剂量施用。在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段每3周施用一次，每次以约1200mg抗TIM-3抗体或其抗原结合片段的剂量施用。
在一些实施方案中，在所述方法或用途中，所述抗PD-1抗体或其抗原结合片段每周(q1w)、每2周(q2w)、每3周(q3w)、或每4周(q4w)施用一次。在一个具体的实施方案中，每2周给予抗PD-1抗体或其抗原结合片段一次。在一个具体的实施方案中，每3周给予抗PD-1抗体或其抗原结合片段一次。在一些实施方案中，所述抗PD-1抗体或其抗原结合片段每次以10-800mg、50-500mg、或100-200mg的剂量施用。在一些实施方案中，所述抗PD-1抗体或其抗原结合片段每次以约10mg、约50mg、约100mg、约120mg、约140mg、约160mg、约180mg、约200mg、约220mg、约240mg、约260mg、约280mg、约300mg、约350mg、约400mg、约450mg、约500mg、约550mg、约600mg、约650mg、约700mg、约750mg、或约800mg、或上述任意值形成的范围的剂量施用。在一些实施方案中，所述抗PD-1抗体或其抗原结合片段每次以约200mg的剂量施用。在一些实施方案中，所述抗PD-1抗体或其抗原结合片段每1周、每2周、每3周、或每4周施用一次，每次以约200mg抗PD-1抗体或其抗原结合片段的剂量施用。在一些实施方案中，所述抗PD-1抗体或其抗原结合片段每2周施用一次，每次以约200mg抗PD-1抗体或其抗原结合片段的剂量施用。在一些实施方案中，所述抗PD-1抗体或其抗原结合片段每3周施用一次，每次以约200mg抗PD-1抗体或其抗原结合片段的剂量施用。
在一些实施方案中，在所述方法或用途中，所述顺铂每周(q1w)、每2周(q2w)、每3周(q3w)、或每4周(q4w)施用一次。在一些实施方案中，在所述方法或用途中，所述顺铂每3周(q3w)施用一次。在一些实施方案中，所述顺铂每次以40-80mg/m2、或40-75mg/m2的剂量施用。在一些实施方案中，所述顺铂每次以40mg/m2、60mg/m2、75mg/m2、80mg/m2、或上述任意值形成的范围的剂量施用。在一些实施方案中，所述顺铂每3周施用一次，每次以40mg/m2、60mg/m2、75mg/m2、80mg/m2顺铂的剂量施用。在一些实施方案中，所述顺铂每3周施用一次，每次以75mg/m2顺铂的剂量施用。在一些实施方案中，所述顺铂每3周施用一次，每次以80mg/m2顺铂的剂量施用。
在一些实施方案中，在所述方法或用途中，所述吉西他滨每周施用一次。在一些实施方案中，所述吉西他滨每次以0.5-1.0g/m2的剂量施用。在一些实施方案中，所述吉西他滨每次以0.5g/m2、0.75g/m2或1.0g/m2的剂量施用。在一些实施方案中，所述吉西他滨以每周一次0.5-1.0g/m2吉西他滨的剂量、连续用药2周、停1周的给药方案给药。在一些实施方案中，所述吉西他滨以每周一次0.5g/m2、0.75g/m2或1.0g/m2吉西他滨的剂量、连续用药2周、停1周的给药方案给药。在一些实施方案中，所述吉西他滨以每周一次1.0g/m2吉西他滨的剂量、连续用药2周、停1周的给药方案给药。
在一些实施方案中，在所述方法或用途中，抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段分别具有相同或不同的治疗周期。在一些具体的实施方案中，抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段具有相同的治疗周期，例如每1周、每2周、每3周、或每4周为一个治 疗周期。在一些具体的实施方案中，抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段具有相同的治疗周期，例如每3周为一个治疗周期。
在一些实施方案中，在所述方法或用途中，抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段、和化疗药物分别具有相同或不同的治疗周期。在一些实施方案中，在所述方法或用途中，抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段、顺铂和吉西他滨分别具有相同或不同的治疗周期。在一些具体的实施方案中，抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段、顺铂和吉西他滨具有相同的治疗周期，例如每1周、每2周、每3周、或每4周为一个治疗周期。在一些具体的实施方案中，抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段、顺铂和吉西他滨具有相同的治疗周期，例如每3周为一个治疗周期。
在一些实施方案中，在所述方法或用途中，每3周为一个治疗周期，在每个治疗周期给予抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段。在一些实施方案中，在所述方法或用途中，每3周为一个治疗周期，在每个治疗周期分别给予抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段一次。在一些实施方案中，在所述方法或用途中，每3周为一个治疗周期，在每个治疗周期的第1天给予抗TIM-3抗体或其抗原结合片段，在每个治疗周期第1天给予抗PD-1抗体或其抗原结合片段。在一些实施方案中，在所述方法或用途中，每3周为一个治疗周期，在每个治疗周期的第1天给予抗TIM-3抗体或其抗原结合片段一次，在每个治疗周期第1天给予抗PD-1抗体或其抗原结合片段一次。
在一些实施方案中，在所述方法或用途中，所述抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段配制在单一制剂中。在一些实施方案中，在所述方法或用途中，每3周为一个治疗周期，在每个治疗周期给予所述单一制剂。在一些实施方案中，在所述方法或用途中，每3周为一个治疗周期，在每个治疗周期给予所述单一制剂一次。在一些实施方案中，在所述方法或用途中，每3周为一个治疗周期，在每个治疗周期第1天给予所述单一制剂。在一些实施方案中，在所述方法或用途中，每3周为一个治疗周期，在每个治疗周期第1天给予所述单一制剂一次。
在一些具体的实施方案中，在所述方法或用途中，每3周为一个治疗周期，在每个治疗周期给予约1200mg或约1500mg的抗TIM-3抗体或其抗原结合片段，在每个治疗周期给予约200mg的抗PD-1抗体或其抗原结合片段。在一些具体的实施方案中，在所述方法或用途中，每3周为一个治疗周期，在每个治疗周期的第1天给予约1200mg或约1500mg的抗TIM-3抗体或其抗原结合片段，在每个治疗周期的第1天给予约200mg的抗PD-1抗体或其抗原结合片段。在一些具体的实施方案中，在所述方法或用途中，每3周为一个治疗周期，在每个治疗周期的第1天给予约1200mg的抗TIM-3抗体或其抗原结合片段，在每个治疗周期的第1天给予约200mg的抗PD-1抗体或其抗原结合片段。
在一些实施方案中，在所述方法或用途中，每3周为一个治疗周期，在每个治疗周期给予抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段、和化疗药物。在一些实施方案中，在所述方法或用途中，每3周为一个治疗周期，在每个治疗周期给予抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段、顺铂和吉西他滨。在一些实施方案中，在所述方法或用途中，每3周为一个治疗周期，在每个治疗周期分别给予抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合和顺铂一次，给予吉西他滨两次。在一些实施方案中，在所述方法或用途中，每3周为一个治疗周期，在每个治疗周期的第1天给予抗TIM-3抗体或其抗原结合片段，在每个治疗周期第1天给予抗PD-1抗体或其抗原结合片段，在每个治疗周期第1天给予顺铂，在每个治疗周期的第1天和第8天给予吉西他滨。在一些实施方案中，在所述方法或用途中，每3周为一个治疗周期，在每个治疗周期的第1天给予抗TIM-3抗体或其抗原结合片段一次，在每个治疗周期第1天给予抗PD-1抗体或其抗原结合片段一次，在每个治疗周期第1天给予顺铂一次，在每个治疗周期的第1天和第8天分别给予吉西他滨一次。
在一些实施方案中，在所述方法或用途中，所述抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段配制在单一制剂中。在一些实施方案中，在所述方法或用途中，每3周为一个治疗周期，在每个治疗周期给予所述单一制剂和化疗药物。在一些实施方案中，在所述方法或用途中，每3周为一个治疗周期，在每个治疗周期给予所述单一制剂、顺铂和吉西他滨。在一些实施方案中，在所述方法或用途中，每3周为一个治疗周期，在每个治疗周期给予所述单一制剂一次，给予顺铂一次，给予吉西他滨两次。在一些实施方案中，在所述方法或用途中，每3周为一个治疗周期，在每个治疗周期的第1天给予所述单一 制剂，在每个治疗周期第1天给予顺铂，在每个治疗周期的第1天和第8天给予吉西他滨。在一些实施方案中，在所述方法或用途中，每3周为一个治疗周期，在每个治疗周期的第1天给予所述单一制剂一次，在每个治疗周期第1天给予顺铂一次，在每个治疗周期的第1天和第8天分别给予吉西他滨一次。
在一些具体的实施方案中，在所述方法或用途中，每3周为一个治疗周期，在每个治疗周期给予约1200mg或约1500mg的抗TIM-3抗体或其抗原结合片段，在每个治疗周期给予约200mg的抗PD-1抗体或其抗原结合片段，在每个治疗周期给予75mg/m2的顺铂，在每个治疗周期给予2.0g/m2的吉西他滨。在一些具体的实施方案中，在所述方法或用途中，每3周为一个治疗周期，在每个治疗周期的第1天给予约1200mg或约1500mg的抗TIM-3抗体或其抗原结合片段，在每个治疗周期的第1天给予约200mg的抗PD-1抗体或其抗原结合片段，在每个治疗周期第1天给予75mg/m2的顺铂，在每个治疗周期第1天和第8天分别给予1.0g/m2的吉西他滨。在一些具体的实施方案中，在所述方法或用途中，每3周为一个治疗周期，在每个治疗周期的第1天给予约1200mg的抗TIM-3抗体或其抗原结合片段，在每个治疗周期的第1天给予约200mg的抗PD-1抗体或其抗原结合片段，在每个治疗周期第1天给予75mg/m2的顺铂，在每个治疗周期第1天和第8天分别给予1.0g/m2的吉西他滨。
在一些实施方案中，在每一个治疗周期中，以(0.1-180):1、(0.2-50):1、(0.5-9):1、(3-7.5):1、(4-7.5):1或(6-7.5):1的抗TIM-3抗体或其抗原结合片段:抗PD-1抗体或其抗原结合片段的质量比，向受试者给予抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段；可选地，向受试者进一步给予化疗药物。在一些实施方案中，所述化疗药物为铂类抗肿瘤药物和/或抗代谢类抗肿瘤药物。在一些实施方案中，所述化疗药物为铂类抗肿瘤药物和/或胞嘧啶类抗肿瘤药物。在一些具体实施方案中，所述化疗药物为顺铂和吉西他滨。在一些实施方案中，在每一个治疗周期中，以(0.1-180):1、(0.2-50):1、(0.5-9):1、(3-7.5):1、(4-7.5):1或(6-7.5):1的抗TIM-3抗体或其抗原结合片段:抗PD-1抗体或其抗原结合片段的质量比，向受试者给予抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段；可选地，向受试者进一步给予顺铂和吉西他滨。
在一些实施方案中，在每一个治疗周期中，所述抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段以多剂量或单剂量给予。在一些实施方案中，在每一个治疗周期中，所述抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段均以多剂量给予。在一些实施方案中，在每一个治疗周期中，所述抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段和化疗药物以多剂量或单剂量给予。在一些实施方案中，在每一个治疗周期中，所述抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段、顺铂和吉西他滨以多剂量或单剂量给予。在一些实施方案中，在每一个治疗周期中，所述抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段、顺铂和吉西他滨均以多剂量给予。
在一些实施方案中，在所述方法或用途中，所述抗TIM-3抗体或其抗原结合片段可以选自0.01至50mg/kg、0.1至40mg/kg、0.1至35mg/kg、0.1至30mg/kg、0.1至25mg/kg、0.1至20mg/kg、0.1至15mg/kg、0.1至10mg/kg、1至40mg/kg、1至35mg/kg、1至30mg/kg、1至25mg/kg、1至20mg/kg、1至15mg/kg、1至10mg/kg、1至3mg/kg、3至40mg/kg、3至35mg/kg、3至30mg/kg、3至25mg/kg、3至20mg/kg、3至15mg/kg、3至10mg/kg、10至40mg/kg、10至30mg/kg、10至25mg/kg、或20至25mg/kg的剂量给予受试者；或者以1-2400mg、20-1800mg、100-1800mg、300-1800mg、600-1600mg、700-1600mg、800-1600mg、900-1600mg、1000-1600mg、1100-1600mg、1200-1600mg、1300-1600mg、1400-1600mg、1500-1600mg、600-1500mg、800-1500mg、1000-1500mg、1200-1500mg、600-1200mg、800-1200mg、600mg、900mg、1200mg、1500mg或1800mg的统一剂量施用于受试者。
在一些实施方案中，在所述方法或用途中，所述抗PD-1抗体或其抗原结合片段可以选自0.01至50mg/kg、0.1至40mg/kg、0.1至35mg/kg、0.1至30mg/kg、0.1至25mg/kg、0.1至20mg/kg、0.1至15mg/kg、0.1至10mg/kg、1至30mg/kg、1至25mg/kg、1至20mg/kg、1至15mg/kg、1至10mg/kg、1至8mg/kg、1至5mg/kg、1至3mg/kg、3至30mg/kg、3至25mg/kg、3至20mg/kg、3至15mg/kg、3至10mg/kg、3至8mg/kg、或3至5mg/kg的剂量给予受试者；或者以1-1000mg、10-1000mg、10-800mg、20-800mg、40-800mg、50-700mg、50-600mg、50-500mg、60-500mg、80-500mg、100-500mg、200-500mg、100-500mg、100-400mg、50-350mg、100-300mg、50-200mg、100-200mg、100mg或200mg的统一剂量施用于受试者。
在一些实施方案中，在所述方法或用途中，所述抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段、化疗药物(例如，顺铂或吉西他滨)的给药方案(例如，给药周期、给药剂量及剂量调整)可根据疾病的严重程度、疾病的响应、任何治疗相关的毒性、患者的年龄和健康状态进行调整。例如，可以将抗TIM-3抗体或其抗原结合片段和/或抗PD-1抗体或其抗原结合片段的一个治疗周期调整为4周、5周、6周、7周、8周、9周、10周、11周或12周、13周、14周或15周。
又例如，在一些实施方案中，顺铂的单次给药剂量可以为40-80mg/m2、或40-75mg/m2。在一些实施方案中，顺铂的单次给药剂量可以为40mg/m2、60mg/m2、75mg/m2或80mg/m2。在一些实施方案中，顺铂的单次给药剂量可以为50-200mg。在一些实施方案中，顺铂在单个治疗周期中的给药剂量可以为40-80mg/m2、或40-75mg/m2。在一些实施方案中，顺铂在单个治疗周期中的给药剂量可以为40mg/m2、60mg/m2、75mg/m2、或80mg/m2。在一些实施方案中，顺铂在单个治疗周期中的给药剂量可以为50-200mg。
再例如，在一些实施方案中，吉西他滨的单次给药剂量可以为0.5-1.0g/m2。在一些实施方案中，吉西他滨的单次给药剂量可以为0.5g/m2、0.75g/m2或1.0g/m2。在一些实施方案中，吉西他滨的单次给药剂量可以为0.5-2.5g。在一些实施方案中，吉西他滨在单个治疗周期中的给药剂量可以为1.0-2.0g/m2。在一些实施方案中，吉西他滨在单个治疗周期中的给药剂量可以为1.0g/m2、1.25g/m2、1.5g/m2、1.75g/m2或2.0g/m2。在一些实施方案中，吉西他滨在单个治疗周期中的给药剂量可以为1.0-5.0g。
抗TIM-3抗体或其抗原结合片段
在一些实施方案中，本公开所述的抗TIM-3抗体或其抗原结合片段包含：SEQ ID NO:1或21所示氨基酸序列的重链CDR1(HCDR1)，SEQ ID NO:2或22所示氨基酸序列的HCDR2，SEQ ID NO:3或23所示氨基酸序列的HCDR3，SEQ ID NO:4或24所示氨基酸序列的轻链CDR1(LCDR1)，SEQ ID NO:5或25所示氨基酸序列的LCDR2，和SEQ ID NO:6或26所示氨基酸序列的LCDR3。在一些实施方案中，本公开所述的抗TIM-3抗体或其抗原结合片段包含：SEQ ID NO:1所示氨基酸序列的HCDR1，SEQ ID NO:2所示氨基酸序列的HCDR2，SEQ ID NO:3所示氨基酸序列的HCDR3，SEQ ID NO:4所示氨基酸序列的LCDR1，SEQ ID NO:5所示氨基酸序列的LCDR2，和SEQ ID NO:6所示氨基酸序列的LCDR3。在一些实施方案中，本公开所述的抗TIM-3抗体或其抗原结合片段包含：SEQ ID NO:21所示氨基酸序列的HCDR1，SEQ ID NO:22所示氨基酸序列的HCDR2，SEQ ID NO:23所示氨基酸序列的HCDR3，SEQ ID NO:24所示氨基酸序列的LCDR1，SEQ ID NO:25所示氨基酸序列的LCDR2，和SEQ ID NO:26所示氨基酸序列的LCDR3。抗TIM-3抗体或其抗原结合片段的CDR序列于表1中示出。
表1.抗TIM-3抗体或其抗原结合片段的CDR序列
本领域技术人员应当理解的是，除非另有规定，否则术语给定抗体或其区(例如可变区)的“CDR”或“互补决定区”应理解为涵盖通过任何一种已知方案界定的互补决定区。虽然表1已经示出了CDR序列(其中，SEQ ID NO:1-6所示的CDR区由AbM编号系统定义)，然而，在涉及用本公开具体CDR序列限定抗体时，所述抗体的范围还涵盖了转换为其他任意编号系统定义(例如本领域所公知的Kabat、Chothia、CCG、IMGT或Contact等定义中的一种或几种的结合)的CDR序列限定的抗体。例如，包含下述氨基酸序列的抗TIM-3抗体或其抗原结合片段也涵盖在本公开的抗TIM-3抗体或其抗原结合片段的范围内：SEQ ID NO:1所示氨基酸序列的HCDR1，SEQ ID NO:2所示氨基酸序列的HCDR2，ARRYYGYDAMDY(SEQ ID NO:31)所示氨基酸序列的HCDR3，SEQ ID NO:4所示氨基酸序列的LCDR1，SEQ ID NO:5所示氨基酸序列的LCDR2，和SEQ ID NO:6所示氨基酸序列的LCDR3。
在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段包含氨基酸序列与SEQ ID NO:7或27所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的重链可变区，和氨基酸序列与SEQ ID NO:8或28所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的轻链可变区。在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段包含SEQ ID NO:7所示氨基酸序列的重链可变区，和SEQ ID NO:8所示氨基酸序列的轻链可变区。在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段包含SEQ ID NO:27所示氨基酸序列的重链可变区，和SEQ ID NO:28所示氨基酸序列的轻链可变区。在一些具体的实施方案中，所述抗TIM-3抗体或其抗原结合片段的重链可变区的氨基酸序列如SEQ ID NO:7所示，和轻链可变区的氨基酸序列如SEQ ID NO:8所示。在一些具体的实施方案中，所述抗TIM-3抗体或其抗原结合片段的重链可变区的氨基酸序列如SEQ ID NO:27所示，和轻链可变区的氨基酸序列如SEQ ID NO:28所示。
在一些实施方案中，本公开所述的抗TIM-3抗体或其抗原结合片段包含重链可变区和轻链可变区，其中重链可变区包含HCDR1、HCDR2和HCDR3，轻链可变区包含LCDR1、LCDR2和LCDR3，其中，HCDR1包含SEQ ID NO:1所示氨基酸序列，HCDR2包含SEQ ID NO:2所示氨基酸序列，HCDR3包含SEQ ID NO:3所示氨基酸序列，LCDR1包含SEQ ID NO:4所示氨基酸序列，LCDR2包含SEQ ID NO:5所示氨基酸序列，和LCDR3包含SEQ ID NO:6所示氨基酸序列，并且，重链可变区包含与SEQ ID NO:7具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的氨基酸序列，和轻链可变区包含与SEQ ID NO:8具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的氨基酸序列。
在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段还可包含免疫球蛋白的恒定区，或所述恒定区的片段、类似物、变体或衍生物。在一些实施方案中，所述恒定区包含重链恒定区和轻链恒定区。在一些实施方案中，所述重链恒定区来自人免疫球蛋白重链，例如IgG1、IgG2、IgG3和IgG4或其他类别免疫球蛋白的重链，优选为IgG4的重链。在一些实施方案中，所述轻链恒定区来自人免疫球蛋白轻链，例如人免疫球蛋白的κ轻链或λ轻链。在一些实施方案中，所述恒定区可包含任何文本所述的修饰，例如氨基酸的插入、缺失、取代或化学修饰。在一些实施方案中，所述恒定区包含改变效应功能的突变。在一些实施方案中，所述恒定区的任意氨基酸残基可用任意同种异型(allotype)的氨基酸残基取代。
在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段包含氨基酸序列与SEQ ID NO:9或29所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的重链，和氨基酸序列与SEQ ID NO:10或30所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的轻链。在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段包含SEQ ID NO:9所示氨基酸序列的重链，和SEQ ID NO:10所示氨基酸序列的轻链。在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段包含SEQ ID NO:29所示氨基酸序列的重链，和SEQ ID NO:30所示氨基酸序列的轻链。在一些具体的实施方案中，所述抗TIM-3抗体或其抗原结合片段的重链的氨基酸序列如SEQ ID NO:9所示，和轻链的氨基酸序列如SEQ ID NO:10所示。在一些具体的实施方案中，所述抗TIM-3抗体或其抗原结合片段的重链的氨基酸序列如SEQ ID NO:29所示，和轻链的氨基酸序列如SEQ ID NO:30所示。
在一些实施方案中，本公开的抗TIM-3抗体或其抗原结合片段是公开号为WO2020041520或CN112566936A的专利申请文件中记载的mAb 50B5或其抗原结合片段，或mAb 50B5的嵌合抗体或其抗原结合片段，或mAb 50B5的人源化抗体或其抗原结合片段。
在另一些实施方案中，本公开的抗TIM-3抗体或其抗原结合片段是公开号为WO2020041520或CN112566936A的专利申请文件中记载的mAb 15B4或其抗原结合片段，或mAb 15B4的嵌合抗体或其抗原结合片段，或mAb 15B4的人源化抗体或其抗原结合片段。
在另一些实施方案中，本公开的抗TIM-3抗体或其抗原结合片段选自Sabatolimab、Cobolimab、Surzebiclimab、Lomvastomig、恒瑞医药的SHR-1702、Agenus的INCAGN-2390、药明生物的BC-3402、维立志博的LBL-003、健信生物的LNL-005、或BMS的BMS-986258。
抗PD-1抗体或其抗原结合片段
在一些实施方案中，本公开所述的抗PD-1抗体或其抗原结合片段包含：SEQ ID NO:11所示氨基酸序列的HCDR1，SEQ ID NO:12所示氨基酸序列的HCDR2，SEQ ID NO:13所示氨基酸序列的HCDR3，SEQ ID NO:14所示氨基酸序列的LCDR1，SEQ ID NO:15所示氨基酸序列的LCDR2，和SEQ ID NO:16所示氨基酸序列的LCDR3。抗PD-1抗体或其抗原结合片段CDR序列于表2中示出。
表2.抗PD-1抗体或其抗原结合片段的CDR序列
本领域技术人员应当理解的是，除非另有规定，否则术语给定抗体或其区(例如可变区)的“CDR”或“互补决定区”应理解为涵盖通过任何一种已知方案界定的互补决定区。虽然表2中已经示出了CDR区，然而，在涉及用具体CDR序列限定抗体时，所述抗体的范围涵盖任意编号系统定义(例如本领域所公知的AbM、Kabat、CCG、Chothia、IMGT或Contact等定义中的一种或几种的结合)的CDR序列限定 的抗体。
在一些实施方案中，所述抗PD-1抗体或其抗原结合片段包含氨基酸序列与SEQ ID NO:17所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的重链可变区，和氨基酸序列与SEQ ID NO:18所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的轻链可变区。在一些实施方案中，所述抗PD-1抗体或其抗原结合片段包含SEQ ID NO:17所示氨基酸序列的重链可变区，和SEQ ID NO:18所示氨基酸序列的轻链可变区。在一些具体的实施方案中，所述抗PD-1抗体或其抗原结合片段的重链可变区的氨基酸序列如SEQ ID NO:17所示，和轻链可变区的氨基酸序列如SEQ ID NO:18所示。
在一些实施方案中，本公开所述的抗PD-1抗体或其抗原结合片段包含重链可变区和轻链可变区，其中重链可变区包含HCDR1、HCDR2和HCDR3，轻链可变区包含LCDR1、LCDR2和LCDR3，其中，HCDR1包含SEQ ID NO:11所示氨基酸序列，HCDR2包含SEQ ID NO:12所示氨基酸序列，HCDR3包含SEQ ID NO:13所示氨基酸序列，LCDR1包含SEQ ID NO:14所示氨基酸序列，LCDR2包含SEQ ID NO:15所示氨基酸序列，和LCDR3包含SEQ ID NO:16所示氨基酸序列，并且，重链可变区包含与SEQ ID NO:17具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的氨基酸序列，和轻链可变区包含与SEQ ID NO:18具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的氨基酸序列。
在一些实施方案中，所述抗PD-1抗体或其抗原结合片段还可包含免疫球蛋白的恒定区，或所述恒定区的片段、类似物、变体或衍生物。在一些实施方案中，所述恒定区包含重链恒定区和轻链恒定区。在一些实施方案中，所述重链恒定区来自人免疫球蛋白重链，例如IgG1、IgG2、IgG3和IgG4或其他类别免疫球蛋白的重链，优选为IgG1的重链。在一些实施方案中，所述轻链恒定区来自人免疫球蛋白轻链，例如人免疫球蛋白的κ轻链或λ轻链。在一些实施方案中，所述恒定区可包含任何文本所述的修饰，例如氨基酸的插入、缺失、取代或化学修饰。在一些实施方案中，所述恒定区包含改变效应功能的突变。在一些实施方案中，所述恒定区的任意氨基酸残基可用任意同种异型(allotype)的氨基酸残基取代。
在一些实施方案中，所述抗PD-1抗体或其抗原结合片段包含氨基酸序列与SEQ ID NO:19所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的重链，和氨基酸序列与SEQ ID NO:20所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的轻链。在一些实施方案中，所述抗PD-1抗体或其抗原结合片段包含SEQ ID NO:19所示氨基酸序列的重链，和SEQ ID NO:20所示氨基酸序列的轻链。在一些具体的实施方案中，所述抗PD-1抗体或其抗原结合片段的重链氨基酸序列如SEQ ID NO:19所示，和轻链氨基酸序列如SEQ ID NO:20所示。

在另一些实施方案中，本公开的抗PD-1抗体或其抗原结合片段选自纳武利尤单抗(Nivolumab)、帕博利珠单抗(Pembrolizumab)、特瑞普利单抗(Toripalimab)、信迪利单抗(Sintilimab)、卡瑞利珠单抗(Camrelizumab)、替雷利珠单抗(Tislelizumab)、赛帕利单抗(Zimberelimab)、巴替利单抗(Balstilimab)、杰诺单抗(geptanolimab)、丽珠医药LZM009、西米普利单抗(Cemiplimab)、斯鲁利单抗(Serplulimab)、Prolgolimab、普特利单抗(Pucotenlimab，代号HX008)、Nofazinlimab、Finotonlimab、Dostarlimab、Cetrelimab、齐鲁制药QL1604、Spartalizumab、Retifanlimab、Sasanlimab、Rulonilimab(代号F520)、或尚健生物技术SG001。
含抗体或其抗原结合片段的药物组合物
在一些实施方案中，所述含抗TIM-3抗体或其抗原结合片段的药物组合物的单位剂量为60-1800mg、100-1600mg、120-1600mg、180-1200mg、或240-600mg的抗TIM-3抗体或其抗原结合片段，例如约60mg、约120mg、约160mg、约180mg、约200mg、约240mg、约280mg、约300mg、约320mg、约360mg、约400mg、约420mg、约440mg、约480mg、约520mg、约540mg、约560mg、约600mg、约640mg、约660mg、约680mg、约720mg、约760mg、约780mg、约800mg、约840mg、约880mg、约900mg、约920mg、约960mg、约1000mg、约1020mg、约1040mg、约1080mg、约1120mg、约1140mg、约1160mg、约1200mg、约1240mg、约1260mg、约1280mg、约1320mg、约1360mg、约1380mg、约1400mg、约1440mg、约1480mg、约1500mg、约1520mg、约1560mg、约1600mg、约1620mg、约1640mg、约1680mg、约1720mg、约1740mg、约1760mg、或约1800mg、或上述任意值形成的范围的抗TIM-3抗体或其抗原结合片段。
在一些实施方案中，所述含抗PD-1抗体或其抗原结合片段的药物组合物的单位剂量为10-500mg、50-500mg、50-200mg、或100-200mg的抗TIM-3抗体或其抗原结合片段，例如约10mg、约20mg、约30mg、约40mg、约50mg、约60mg、约70mg、约80mg、约90mg、约100mg、约110mg、约120mg、约130mg、约140mg、约150mg、约160mg、约170mg、约180mg、约190mg、约200mg、约210mg、约220mg、约230mg、约240mg、约250mg、约260mg、约270mg、约280mg、约290mg、约300mg、约310mg、约320mg、约330mg、约340mg、约350mg、约360mg、约370mg、约380mg、约390mg、约400mg、约410mg、约420mg、约430mg、约440mg、约450mg、约460mg、约470mg、约480mg、约490mg、约500mg、或上述任意值形成的范围的抗TIM-3抗体或其抗原结合片段。
在一些实施方案中，所述含抗TIM-3抗体或其抗原结合片段的药物组合物中还可包含一种或多种医药上可接受的赋形剂以制成合适的制剂。在一些实施方案中，所述含抗PD-1抗体或其抗原结合片段的药物组合物中还可包含一种或多种医药上可接受的赋形剂以制成合适的制剂。所述制剂包括但不限于，片剂、含片、丸剂、胶囊剂(例如硬胶囊、软胶囊、肠溶胶囊、微囊剂)、酏剂、颗粒剂、糖浆剂、注射剂(即适合注射的制剂，例如适合肌肉内、静脉内、腹腔内、皮下注射的制剂)、颗粒剂、乳剂、悬浮液、溶液、分散剂和用于口服或非口服给药的缓释制剂。
在一些实施方案中，抗TIM-3抗体或其抗原结合片段和/或抗PD-1抗体或其抗原结合片段配制为用于胃肠外途径施用的制剂。在一些具体的实施方案中，抗TIM-3抗体或其抗原结合片段和/或抗PD-1抗体或其抗原结合片段配制为用于静脉内、肌肉内、皮下或其它胃肠外途径施用的制剂。在一些具体的实施方案中，抗TIM-3抗体或其抗原结合片段和/或抗PD-1抗体或其抗原结合片段配制为用于静脉内、肌肉内或皮下施用的制剂。在一些具体的实施方案中，抗TIM-3抗体或其抗原结合片段和/或抗PD-1抗体或其抗原结合片段可以配制成注射剂。在一些具体的实施方案中，抗TIM-3抗体或其抗原结合片段和/或抗PD-1抗体或其抗原结合片段配制为用于静脉注射或输注的制剂。
在一些实施方案中，抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段配制在单一制剂中。在一些实施方案中，抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段与一种或多种医药上可接受的赋形剂配制在一起以制成合适的药物组合物。
在一些实施方案中，抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段分开配制(即，各自呈药物组合物的形式)。在一些实施方案中，抗TIM-3抗体或其抗原结合片段与一种或多种医药上可 接受的赋形剂配制在一起以制成合适的药物组合物。在一些实施方案中，抗PD-1抗体或其抗原结合片段与一种或多种医药上可接受的赋形剂配制在一起以制成合适的药物组合物。
本文所用的“赋形剂”用于描述除了本公开的化合物以外的任何成分。赋形剂的选择，在很大程度上将取决于诸如特定的施用方式、赋形剂对溶解度和稳定性的功效以及剂型的性质等因素。如本文所用的，“医药上可接受的赋形剂”包括生理上相容的任何和全部的溶剂、分散介质、包衣、抗细菌和抗真菌剂、等渗剂和吸收延迟剂等等。医药上可接受的赋形剂的一些实例为水、盐水、右旋糖、甘油、乙醇等及其组合。在许多情况下，药物组合物中包含等渗剂。医药上可接受的赋形剂的其他实例为润湿剂或少量的辅助物质，诸如润湿剂或乳化剂，防腐剂或缓冲剂，其提高抗体的储存期或有效性。
在一个具体实施方案中，所述含抗TIM-3抗体或其抗原结合片段的药物组合物为水溶性注射液。在一个具体实施方案中，所述含抗PD-1抗体或其抗原结合片段的药物组合物为水溶性注射液。在一个具体实施方案中，所述含抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段的药物组合物为水溶性注射液。所述水溶性注射液包括但不限于未经冻干的水溶性制剂或冻干粉重构的水溶性制剂。
在另一些实施方案中，所述含抗TIM-3抗体或其抗原结合片段的药物组合物为冻干制剂。在另一些实施方案中，所述含抗PD-1抗体或其抗原结合片段的药物组合物为冻干制剂。在一个具体实施方案中，所述含抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段的药物组合物为冻干制剂。所述冻干制剂是指水溶液经历冻干过程制备的制剂，在该过程中物质首先被冷冻，然后先通过升华降低溶剂数量(初级干燥过程)，然后通过脱附作用降低溶剂数量(二级干燥过程)，直到溶剂数量为不再支持生物学活性或化学反应的值。本公开的冻干制剂还可以通过本领域已知的其它方法干燥，如喷雾干燥和鼓泡干燥(bubble drying)。
在一些实施方案中，所述含抗PD-1抗体或其抗原结合片段的药物组合物中抗PD-1抗体或其抗原结合片段的浓度为0.1-50mg/mL、0.5-30mg/mL、0.8-20mg/mL、1-15mg/mL、1-10mg/mL、1-5mg/mL、2-20mg/mL、2-15mg/mL、2-10mg/mL、或2-5mg/mL。在一些具体的实施方案中，抗PD-1抗体或其抗原结合片段的浓度为约0.8mg/mL、约1mg/mL、约2mg/mL、约3mg/mL、约4mg/mL、约5mg/mL、约6mg/mL、约7mg/mL、约8mg/mL、约9mg/mL、约10mg/mL、约15mg/mL、或约20mg/mL。在一些实施方案中，抗PD-1抗体或其抗原结合片段的浓度为约1mg/mL。在一些实施方案中，抗PD-1抗体或其抗原结合片段的浓度为约2mg/mL。在一些实施方案中，抗PD-1抗体或其抗原结合片段的浓度为约5mg/mL。在一些实施方案中，抗PD-1抗体或其抗原结合片段的浓度为约10mg/mL。
在一些实施方案中，所述抗PD-1抗体或其抗原结合片段呈药物组合物形式，其包含抗PD-1抗体或其抗原结合片段、缓冲剂、等渗调节剂/稳定剂、和表面活性剂。在一个具体实施方案中，所述抗PD-1抗体或其抗原结合片段呈液体药物组合物形式(例如注射液)，其包含抗PD-1抗体或其抗原结合片段、三水合乙酸钠、冰醋酸、山梨醇和聚山梨酯80。
化疗药物
在本公开一些实施方案中，所述化疗药物包括但不限于铂类抗肿瘤药物(包括但不限于奥沙利铂、顺铂、卡铂、奈达铂、双环铂、米铂、洛铂、吡铂(picoplatin)、乐铂(Lobaplatin)、四硝酸三铂、菲铂、沙铂)、喜树碱类抗肿瘤药物(包括但不限于喜树碱、羟基喜树碱、氨基喜树碱、伊立替康、拓扑替康、依喜替康、鲁比替康、勒托替康(lurtotecan)、吉马替康、karenitecin、7-乙基喜树碱)、紫杉烷类抗肿瘤药物(包括但不限于紫杉醇、紫杉醇脂质体、白蛋白结合的紫杉醇以及多西他赛)、氮芥类抗肿瘤药物(包括但不限于环磷酰胺、异环磷酰胺、苯丁酸氮芥、卡氮芥、美法仑、苯达莫司汀)、抗代谢类抗肿瘤药物(包括但不限于氟尿嘧啶类抗肿瘤药物(包括但不限于卡莫氟、5-氟尿嘧啶、替加氟、卡培他滨、替吉奥、双呋氟尿嘧啶、去氧氟尿苷、三氟尿苷)、胞嘧啶类抗肿瘤药物(包括但不限于阿糖胞苷、吉西他滨、阿扎胞苷、安西他滨)、嘌呤类抗肿瘤药物(包括但不限于巯嘌呤、氟达拉滨)、抗叶酸类抗肿瘤药物(包括但不限于甲氨蝶呤、培美曲塞))、蒽环类抗肿瘤药物(包括但不限于多柔比星、表柔比星、吡柔比星、氨柔比星、阿柔比星、伊达比星、柔红霉素、米托蒽醌、伊达柔比星、戊柔比星、佐柔比星、匹杉琼、脂质体阿霉素)、长春碱类抗肿瘤药物(包括但不限于长春碱、长春新碱、长春地辛、长春富宁(vinflunine)和长春瑞滨)、鬼臼生物碱类抗肿瘤药物(包括但不限于依托泊苷、替尼泊苷)、激素类抗肿瘤药物(包括但不限于泼尼松、泼尼松龙、地塞米松、甲泼尼龙琥珀酸钠)、甲基苄肼、六甲嘧胺、达卡巴嗪、丝裂霉素、放线菌素D(更 生霉素)、博来霉素、平阳霉素、替莫唑胺、氨烯咪胺、培洛霉素、艾日布林、普那布林(plinabulin)、Sapacitabine、曲奥舒凡(treosulfan)、153Sm-EDTMP、和encequidar中的一种或多种。
在一些实施方案中，所述化疗药物选自铂类抗肿瘤药物、紫杉烷类抗肿瘤药物、以及抗代谢类抗肿瘤药物中的一种或多种。在一些实施方案中，所述化疗药物为铂类抗肿瘤药物和/或抗代谢类抗肿瘤药物。在一些实施方案中，所述化疗药物为铂类抗肿瘤药物和/或胞嘧啶类抗肿瘤药物。
进一步地，所述铂类抗肿瘤药物选自顺铂、卡铂、奈达铂、双环铂、吡铂、奥沙利铂、米铂、洛铂、乐铂、四硝酸三铂、菲铂或沙铂中的一种或多种，优选为卡铂和/或顺铂，更优选为顺铂。
在一些实施方案中，所述抗代谢类抗肿瘤药物选自阿糖胞苷、吉西他滨、阿扎胞苷或安西他滨中的一种或多种，优选为吉西他滨。在一些实施方案中，所述胞嘧啶类抗肿瘤药物选自阿糖胞苷、吉西他滨、阿扎胞苷或安西他滨中的一种或多种，优选为吉西他滨。
在一些实施方案中，所述化疗药物为铂类抗肿瘤药物和抗代谢类抗肿瘤药物。在一些实施方案中，所述化疗药物为铂类抗肿瘤药物和胞嘧啶类抗肿瘤药物。在一些具体的实施方案中，所述化疗药物为顺铂和吉西他滨。
在一些实施方案中，所述化疗药物按照已知的给药方案(包括给药周期、给药剂量及剂量调整、给药途径)给药。
吉西他滨
如本公开所用，吉西他滨的化学名为2’-脱氧-2’,2’-二氟胞苷(β-异构体)，其具有式(I)的结构式：
如本公开所用，吉西他滨包括其游离碱形式，也包括药学上可接受的盐，所述非盐形式或盐都纳入本公开的保护范围内。吉西他滨可以以其游离碱形式给药，也可以以其药学上可接受的盐的形式给药。例如吉西他滨的药学上可接受的盐在本公开的范围内，可按照本领域公知的方法由不同的有机酸和无机酸产生所述盐，例如无机酸可选自盐酸、氢溴酸、硫酸、硝酸或磷酸，有机酸可选自琥珀酸、马来酸、乙酸、富马酸、柠檬酸、酒石酸、苯甲酸、对甲苯磺酸或甲磺酸。在一些实施方案中，吉西他滨的药学上可接受的盐可以是吉西他滨的盐酸盐。
在本公开的一些实施方案中，吉西他滨以其盐酸盐的形式给药。在一些实施方案中，吉西他滨以其一盐酸盐的形式给药。
本公开中涉及的吉西他滨的剂量，除非另有说明，均基于式(I)化合物的分子量。
含化疗药物的药物组合物
在本公开的一些实施方案中，所述含顺铂的药物组合物的单位剂量为2.5mg、5mg、10mg、20mg、25mg、30mg、50mg和/或100mg的顺铂。在一些实施方案中，所述含顺铂的药物组合物的单位剂量为20mg、30mg和/或100mg的顺铂。在一些实施方案中，所述含顺铂的药物组合物的单位剂量为30mg的顺铂。
在本公开的一些实施方案中，所述含吉西他滨的药物组合物的单位剂量为0.2mg或1.0mg的吉西他滨。
在一些实施方案中，所述含顺铂的药物组合物为适合注射的制剂。在一些实施方案中，所述含顺铂的药物组合物为液体制剂。在一些实施方案中，所述含顺铂的药物组合物为适合注射的液体制剂。在一些实施方案中，所述含顺铂的药物组合物为适合静脉注射的液体制剂。在一些实施方案中，所述含顺铂的药物组合物为冻干制剂。在一些实施方案中，所述含顺铂的药物组合物为粉剂。
在一些实施方案中，所述含吉西他滨的药物组合物为适合注射的制剂。在一些实施方案中，所述含吉 西他滨的药物组合物为液体制剂。在一些实施方案中，所述含吉西他滨的药物组合物为适合注射的液体制剂。在一些实施方案中，所述含吉西他滨的药物组合物为适合静脉注射的液体制剂。在一些实施方案中，所述含吉西他滨的药物组合物为冻干制剂。在一些实施方案中，所述含吉西他滨的药物组合物为粉剂。
所述适合注射的液体制剂可使用本领域公知的药学上可接受的载体通过常规方法制得。药学上可接受的载体包括填充剂、吸收剂、润湿剂、粘合剂、崩解剂、润滑剂等。在一个特定实施方案中，所述适合注射的含顺铂的液体制剂的药学上可接受的载体包括聚乙二醇400和氯化钠。在一个特定实施方案中，所述适合注射的含吉西他滨的液体制剂的药学上可接受的载体包括甘露醇、醋酸钠、盐酸和氢氧化钠。
施用方式
下述内容并非限制本公开的药物组合的施用方式。
本公开的药物组合中的各组分可以各自独立地、或者其中的部分或全部共同以适合的各种途径施用，包括但不限于，口服或胃肠外途径(例如，通过静脉内、肌内、局部或皮下途径)施用。在一些实施方案中，本公开的药物组合的各组分可以各自独立地、或者其中的部分或全部共同口服施用或注射施用，例如通过静脉注射或皮下注射。
本公开的药物组合中的组分可以各自独立地、或者其中的部分或全部共同配制成适合的剂型，包括但不限于，片剂、含片、丸剂、胶囊剂(例如硬胶囊、软胶囊、肠溶胶囊、微囊剂)、酏剂、颗粒剂、糖浆剂、注射剂(肌肉内、静脉内、腹腔内、皮下)、颗粒剂、粉剂、乳剂、悬浮液、溶液、分散剂和用于口服或非口服给药的缓释制剂的剂型。在一些实施方案中，本公开的药物组合的各组分可以各自独立地、或者其中的部分或全部共同配制成注射剂。
本公开的药物组合中的组分可以各自独立地、或者其中的部分或全部共同含有药学上可接受的载体和/或赋形剂。
本公开的药物组合还可以包含另外的治疗剂。在一个实施方案中，所述另外的治疗剂可以是本领域已知的肿瘤治疗剂。
肿瘤
在某些方面，本公开所述肿瘤为恶性肿瘤(即癌症)；所述恶性肿瘤是指由异常细胞生长引起的任何恶性和/或侵袭性生长。在一些实施方案中，所述肿瘤是实体瘤。在一些实施方案中，所述肿瘤是初治的、难治性的、复发性的、转移性的和/或晚期的实体瘤。在一些实施方案中，所述肿瘤为复发和/或转移性的实体瘤。
在一些实施方案中，所述肿瘤为鼻咽癌。在一些实施方案中，所述肿瘤是初治的、难治性的、复发性的、转移性的和/或晚期的鼻咽癌。在一些实施方案中，所述肿瘤为初治的鼻咽癌。在一些实施方案中，所述肿瘤为晚期鼻咽癌。在一些实施方案中，所述肿瘤为晚期初治鼻咽癌。在一些实施方案中，所述肿瘤为复发性的鼻咽癌。在一些实施方案中，所述肿瘤为转移性的鼻咽癌。在一些实施方案中，所述肿瘤为复发和/或转移性的鼻咽癌。
在一些实施方案中，所述鼻咽癌是分化型或未分化型鼻咽癌。在一些实施方案中，所述鼻咽癌是角化性或非角化性鼻咽癌。在一些实施方案中，所述鼻咽癌是未分化型非角化性鼻咽癌。在一些实施方案中，所述鼻咽癌是未分化型非角化性晚期鼻咽癌。在一些实施方案中，所述鼻咽癌是未分化型非角化性复发和/或转移性鼻咽癌。
在一些实施方案中，所述鼻咽癌为Ⅳ期鼻咽癌。在一些实施方案中，所述鼻咽癌为Ⅳb期鼻咽癌。在一些实施方案中，所述鼻咽癌为不适合局部治疗的鼻咽癌。在一些实施方案中，所述鼻咽癌为Ⅳb期或不适合局部治疗的复发性鼻咽癌。
在一些实施方案中，所述鼻咽癌的主体先前未治疗过鼻咽癌(例如，缺乏有效的治疗方案)。在一些实施方案中，所述鼻咽癌的主体既往未接受过系统治疗以治疗鼻咽癌(例如，既往未接受过系统性治疗以治疗晚期初治鼻咽癌)。在一些实施方案中，所述鼻咽癌的主体既往未接受过放射疗法、化学疗法和/或免疫疗法以治疗鼻咽癌。
在一些实施方案中，所述鼻咽癌为晚期初治鼻咽癌，所述晚期初治鼻咽癌的主体既往未接受过系统性治疗以治疗鼻咽癌。在一些实施方案中，所述鼻咽癌为晚期初治鼻咽癌，所述晚期初治鼻咽癌的主体既往未接受过放射疗法、化学疗法和/或免疫疗法以治疗鼻咽癌。在一些实施方案中，所述鼻咽癌为晚期初治鼻 咽癌，所述晚期初治鼻咽癌的主体既往未接受过免疫检查点(例如，PD-1或PD-L1)抑制剂以治疗鼻咽癌。在一些实施方案中，所述鼻咽癌为晚期初治鼻咽癌，所述晚期初治鼻咽癌的主体既往未接受过系统性治疗和免疫检查点(例如，PD-1或PD-L1)抑制剂以治疗鼻咽癌。
在一些实施方案中，所述鼻咽癌为复发和/或转移性鼻咽癌，所述复发和/或转移性鼻咽癌的主体既往未接受过系统性治疗以治疗鼻咽癌。在一些实施方案中，所述鼻咽癌为复发和/或转移性鼻咽癌，所述复发和/或转移性鼻咽癌的主体既往未接受过放射疗法、化学疗法和/或免疫疗法以治疗鼻咽癌。在一些实施方案中，所述鼻咽癌为复发和/或转移性鼻咽癌，所述复发和/或转移性鼻咽癌的主体既往未接受过免疫检查点(例如，PD-1或PD-L1)抑制剂以治疗鼻咽癌。在一些实施方案中，所述鼻咽癌为复发和/或转移性鼻咽癌，所述复发和/或转移性鼻咽癌的主体既往未接受过系统性治疗和免疫检查点(例如，PD-1或PD-L1)抑制剂以治疗鼻咽癌。
在一些实施方案中，所述鼻咽癌的主体既往未接受过系统性治疗以治疗鼻咽癌。在一些实施方案中，所述复发和/或转移性鼻咽癌的主体既往未接受过系统性治疗以治疗复发和/或转移性鼻咽癌。在一些实施方案中，所述晚期鼻咽癌的主体既往未接受过系统性治疗以治疗晚期鼻咽癌。
在一些实施方案中，所述鼻咽癌的主体既往未接受过免疫检查点抑制剂治疗以治疗鼻咽癌。在一些实施方案中，所述复发和/或转移性鼻咽癌的主体既往未接受过免疫检查点抑制剂治疗以治疗复发和/或转移性鼻咽癌。在一些实施方案中，所述晚期鼻咽癌的主体既往未接受过免疫检查点抑制剂治疗以治疗晚期鼻咽癌。
在一些实施方案中，所述鼻咽癌的主体先前已经用一种或多种不同的抗肿瘤治疗方法治疗过鼻咽癌(例如，治疗失败或不耐受)。在一些实施方案中，所述鼻咽癌的主体既往接受过全身系统性治疗方案治疗过鼻咽癌(例如，治疗失败或不耐受)。在一些实施方案中，所述鼻咽癌的主体既往接受过至少一线全身系统性治疗方案治疗过鼻咽癌(例如，治疗失败或不耐受)。在一些实施方案中，所述鼻咽癌的主体既往接受过新辅助治疗或辅助治疗、以及根治性同步放化疗以治疗鼻咽癌(例如，治疗失败或不耐受)。在一些实施方案中，所述鼻咽癌的主体在局部晚期阶段接受过免疫检查点抑制剂以治疗鼻咽癌(例如，治疗失败或不耐受)。
在一些实施方案中，所述鼻咽癌为复发和/或转移性鼻咽癌，所述复发和/或转移性鼻咽癌的主体既往接受过全身系统性治疗方案治疗过鼻咽癌(例如，治疗失败或不耐受)。在一些实施方案中，所述鼻咽癌为复发和/或转移性鼻咽癌，所述复发和/或转移性鼻咽癌的主体既往接受过至少一线全身系统性治疗方案治疗过鼻咽癌(例如，治疗失败或不耐受)。在一些实施方案中，所述鼻咽癌为复发和/或转移性鼻咽癌，所述复发和转移性鼻咽癌的主体既往接受过新辅助治疗或辅助治疗、以及根治性同步放化疗以治疗鼻咽癌(例如，治疗失败或不耐受)。在一些具体的实施方案中，所述复发和/或转移性鼻咽癌的主体既往接受过新辅助治疗或辅助治疗、以及根治性同步放化疗以治疗鼻咽癌，且在治疗期间或停止治疗后6个月内(例如2、3、4、5或6个月)疾病进展。在一些实施方案中，所述复发和/或转移性鼻咽癌的主体在局部晚期阶段接受过免疫检查点抑制剂以治疗鼻咽癌(例如，治疗失败或不耐受)。
在一些实施方案中，所述鼻咽癌为晚期鼻咽癌，所述晚期鼻咽癌的主体既往接受过全身系统性治疗方案治疗过鼻咽癌(例如，治疗失败或不耐受)。在一些实施方案中，所述鼻咽癌为晚期鼻咽癌，所述晚期鼻咽癌的主体既往接受过至少一线全身系统性治疗方案治疗过鼻咽癌(例如，治疗失败或不耐受)。在一些实施方案中，所述鼻咽癌为晚期鼻咽癌，所述晚期鼻咽癌的主体既往接受过新辅助治疗或辅助治疗、以及根治性同步放化疗以治疗鼻咽癌(例如，治疗失败或不耐受)。在一些具体的实施方案中，所述晚期鼻咽癌的主体既往接受过新辅助治疗或辅助治疗、以及根治性同步放化疗以治疗鼻咽癌，且在治疗期间或停止治疗后6个月内(例如2、3、4、5或6个月)疾病进展。
在一些实施方案中，所述鼻咽癌的主体先前已经用放射疗法、化学疗法和免疫疗法中的一种或多种治疗过鼻咽癌(例如治疗失败或不耐受)。在一些实施方案中，所述鼻咽癌的主体既往接受过铂类抗肿瘤药物以治疗鼻咽癌(例如，治疗失败)。在一些实施方案中，所述鼻咽癌的主体既往接受过免疫检查点(例如，PD-1或PD-L1)抑制剂以治疗鼻咽癌(例如，治疗失败或不耐受)。在一些实施方案中，所述鼻咽癌的主体既往接受过铂类抗肿瘤药物和免疫检查点(例如，PD-1或PD-L1)抑制剂以治疗鼻咽癌(例如，治疗失败或不耐受)。
在一些实施方案中，所述鼻咽癌为免疫检查点抑制剂治疗失败的鼻咽癌。在一些实施方案中，所述鼻咽癌为免疫检查点抑制剂治疗失败的复发和/或转移性鼻咽癌。在一些实施方案中，所述鼻咽癌为免疫检查点抑制剂治疗失败的晚期鼻咽癌。
在一些具体的实施方案中，所述鼻咽癌为复发和/或转移性鼻咽癌，所述复发和/或转移性鼻咽癌的主体既往接受过铂类抗肿瘤药物和免疫检查点(例如，PD-1或PD-L1)抑制剂以治疗鼻咽癌(例如，治疗失败或不耐受)。在一些具体的实施方案中，所述鼻咽癌为复发和/或转移性鼻咽癌，所述复发和/或转移性鼻咽癌的主体既往接受过铂类抗肿瘤药物和免疫检查点(例如，PD-1或PD-L1)抑制剂以治疗鼻咽癌，且在治疗期间或停止治疗后6个月内(例如2、3、4、5或6个月)疾病进展。
在一些具体的实施方案中，所述鼻咽癌为晚期鼻咽癌，所述晚期鼻咽癌的主体既往接受过铂类抗肿瘤药物和免疫检查点(例如，PD-1或PD-L1)抑制剂以治疗鼻咽癌(例如，治疗失败或不耐受)。在一些具体的实施方案中，所述鼻咽癌为晚期鼻咽癌，所述晚期鼻咽癌的主体既往接受过铂类抗肿瘤药物和免疫检查点(例如，PD-1或PD-L1)抑制剂以治疗鼻咽癌，且在治疗期间或停止治疗后6个月内(例如2、3、4、5或6个月)疾病进展。
在一些实施方案中，所述免疫检查点(例如，PD-1或PD-L1)抑制剂为针对免疫检查点(例如，PD-1或PD-L1)的抗体或其抗原结合片段，例如：纳武利尤单抗(Nivolumab)、帕博利珠单抗(Pembrolizumab)、特瑞普利单抗(Toripalimab)、信迪利单抗(Sintilimab)、卡瑞利珠单抗(Camrelizumab)、替雷利珠单抗(Tislelizumab)、巴替利单抗(Balstilimab)、赛帕利单抗(Zimberelimab)、阿替利珠单抗(Atezolizumab)、度伐利尤单抗(Durvalumab)、阿利库单抗(Avelumab)、恩沃利单抗(Envafolimab)或舒格利单抗(Sugemalimab)。
在一些实施方案中，所述铂类抗肿瘤药物包括但不限于顺铂、卡铂、奈达铂、双环铂、吡铂、奥沙利铂、米铂、洛铂、乐铂、四硝酸三铂、菲铂或沙铂中的一种或多种。
技术效果
通常，使用上述的本公开的药物组合将有助于：
(1)与单独给予该组合中的任一药物相比，在减少肿瘤的生长或甚至消除肿瘤方面产生更好的疗效；
(2)与该组合中的任一药物单独给药相比，提供更少量的给药；
(3)提供在患者中具有良好耐受的治疗，与单一给予的任一药物相比，其不良反应和/或并发症更少；
(4)提供在所治疗患者之中的更好的疾病控制率；
(5)提供在所治疗的患者具有更长的生存期(例如中位生存期、无进展生存期或总生存期)；
(6)提供相比于标准的化疗而言，所治疗患者具有更长的生存期(例如中位生存期、无进展生存期或总生存期)；
(7)提供更长时间的疾病缓解持续时间(DOR)；和/或
(8)与单独给予该组合中的任一药物相比，具有良好的抗肿瘤的活性，表现出更优异的抗肿瘤协同效果。
本公开的药物组合及治疗方案，在治疗鼻咽癌，尤其是复发和/或转移性鼻咽癌中具有较好的疗效。其中至少在ORR、DCR、DOR、PFS、OS、耐受性和副作用中的至少一方面具有有益的效果。
定义和说明
除非另有说明，本公开中所用的下列术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本公开中出现商品名时，意在指代其对应的商品或其活性成分。
如文本所用，术语“药物组合”是指同时或先后施用的两种或两种以上的活性成分(包括以各自的活性成分本身的形式施用，或者以其各自的药学上可接受的盐或酯等衍生物、前药或组合物的形式施用)的组合。所述活性成分可以各自作为单一制剂同时地、或各自作为单一制剂以任何顺序依次地施用于受试者。或者，所述活性成分的全部配制在单一制剂中，同时施用于受试者。或者，所述活性成分的部分配制在单一制剂中、且所述活性成分中的其他部分各自作为单一制剂，同时地、或以任何顺序依次地施用于受试者。
术语“固定组合”指活性组分以固定总剂量或剂量比例，或以单一实体、药物组合物或制剂的形式同时给予受试者。
术语“非固定组合”指两种以上活性组分作为独立的实体(例如药物组合物、制剂)同时、并行或依 序地给予受试者，其中所述给予受试者的活性成份达到治疗有效量水平。非固定组合可列举的例子是鸡尾酒疗法，例如给予3种或以上之活性组分。在非固定组合中，所述各个活性组分可以作为完全独立的药物组合物进行包装、销售或给药。所述“非固定组合”也包括“固定组合”之间、或“固定组合”与任一或多种活性组分的独立实体的联合使用。
如本文所用，术语“抗体”是指具有至少一个抗原结合结构域的抗原结合蛋白。本公开的抗体和其片段可以是整个抗体或其任何片段。因此，本公开的抗体和其片段包括单克隆抗体或其片段和抗体变体或其片段。抗体和其抗原结合片段片段的实例包括单特异性抗体、双特异性抗体、多特异性抗体、Fab片段、Fab'片段、F(ab)'2片段、Fv片段、分离的CDR区、单链Fv分子(scFv)和本领域已知的其它抗体片段。本文公开的抗TIM-3抗体和抗PD-1抗体和其抗原结合片段可以是IgG1、IgG2、IgG3或IgG4同种型。术语“同种型”是指由重链恒定区基因编码的抗体种类。本公开的抗TIM-3抗体和其抗原结合片段以及抗PD-1抗体和其抗原结合片段可以衍生自任何物种，包括但不限于小鼠、大鼠、兔、灵长类动物、美洲驼和人。本公开的抗TIM-3抗体和其抗原结合片段以及抗PD-1抗体和其抗原结合片段可以是鼠类抗体、嵌合抗体、人源化抗体或全人源抗体。除非另有说明，否则本公开的“抗体”包括整个抗体及其任何抗原结合片段(或“抗原结合部分”)或单链。常规的“整个抗体”是包含两条重(H)链和两条轻(L)链的糖蛋白，重链和轻链通过二硫键连接。每条重链由重链可变区(VH)和重链恒定区(CH)组成。重链恒定区由三个结构域组成，即CH1，CH2和CH3。每条轻链由轻链可变区(VL)和轻链恒定区(CL)组成。轻链恒定区由一个结构域CL组成。VH和VL区还可以划分为高变区，即互补决定区(CDR)，和序列较为保守的框架区(FR)。每个VH和VL分别由三个CDR和四个FR组成，从氨基端到羧基端分别为：FR1，CDR1，FR2，CDR2，FR3，CDR3，FR4。重链和轻链的可变区包含与抗原相互作用的结合域。抗体的恒定区可以介导免疫球蛋白与宿主组织或因子的结合，所述宿主组织或因子包括免疫系统的多种细胞(例如，效应细胞)和经典补体系统的第一成分(C1q)。与此同时，如本领域技术人员所了解的，特殊的“整个抗体”，例如纳米抗体，其仅只有重(H)链而没有轻(L)链。
抗体的“抗原结合片段”或“抗体结合部分”是指抗体的一个或多个片段，其保留特异性结合抗原(例如，TIM-3或PD-1)的功能。已证实，抗体的抗原结合功能可以通过整个抗体的片段来实施。涵盖在术语抗体的“抗原结合部分/片段”中的实例包括：(i)Fab片段：由VL、VH、CL和CH1结构域组成的单价片段；(ii)F(ab')2片段，包含在铰链区二硫桥连接的两个Fab片段的二价片段；(iii)由VH和CH1结构域组成的Fd片段；(iv)由抗体单臂的VL和VH结构域组成的Fv片段；(v)由VH结构域组成的dAb片段(参见Ward et al.,Nature.341:544-546(1989))；(vi)分离的互补决定区(CDR)；以及(vii)纳米抗体，一种包含单可变结构域和两个恒定结构域的重链可变区。此外，尽管Fv片段的两个结构域VL和VH由不同基因编码，但可以采用重组的方法通过合成接头将VH和VL连接成单蛋白链，其中VL和VH配对形成单价分子(称单链Fv(scFv)；参见例如Bird et al.,Science.242:423-426(1988)；Huston et al.,Proc.Natl.Acad.Sci.85:5879-5883(1988))。这些单链抗体也涵盖在术语抗原结合部分/片段中。此外，包含该抗原结合部分/片段的重组多肽、融合蛋白和免疫缀合物也涵盖在术语抗原结合部分/片段中。
“嵌合抗体”是下述抗体：所述抗体具有衍生自一种物种的重链可变区的至少一部分和轻链可变区的至少一部分；以及衍生自另一物种的恒定区的至少一部分。例如，在一个实施方案中，嵌合抗体可以包含鼠类可变区和人恒定区。
“人源化抗体”是下述抗体：所述抗体含有衍生自非人抗体的互补决定区(CDR)以及衍生自人抗体的框架区和恒定区。例如，抗TIM-3抗体以及抗PD-1抗体可以包含衍生自一种或多种鼠类抗体的CDR以及人框架区和人恒定区。本文提供了示例性人源化抗体。包含本文提供的HCDR和LCDR的另外的抗TIM-3抗体或其变体可以使用任何人框架序列产生，并且也包括在本公开中。包含本文提供的HCDR和LCDR的另外的抗PD-1抗体或其变体可以使用任何人框架序列产生，并且也包括在本公开中。在一个实施方案中，适用于在本公开中使用的框架序列包括在结构上与本文提供的框架序列类似的那些框架序列。可以在框架区中进行另外修饰以改进本文提供的抗体的特性。此类另外的框架修饰可以包括化学修饰；点突变以降低免疫原性或去除T细胞表位；或使突变回复为原始种系序列中的残基。在一些实施方案中，此类修饰包括对应于本文示例的突变的那些修饰，包括对种系序列的回复突变。例如，在一个实施方案中，本文提供的人源化抗体的VH和/或VL的人框架区中的一个或多个氨基酸被回复突变为亲本鼠类抗体中对应的氨基酸。
术语“同一性”，也称一致性。氨基酸序列的“同一性百分数(％)”是指将待比对序列与本文中所示的具体氨基酸序列进行比对并且如有必要的话为达到最大序列同一性百分数而引入空位后，并且不考虑任何保守置换作为序列同一性的一部分时，待比对序列中与本文中所示的具体氨基酸序列的氨基酸残基相同的氨基酸残基百分数。同一性的氨基酸序列比对可以采用本领域范围内的多种方式进行，例如BLAST、BLAST-2、ALIGN或Megalign(DNASTAR)软件。本领域技术人员可决定用于比对序列的适宜参数，包括在比较序列的全长里获得最大比对需要的任何算法。
术语“治疗”指试图改变治疗个体中疾病的自然进程，并且可以是为了预防、改善或消除疾病或与所述疾病相关的一个或多个症状，包括但不限于预防疾病的发生或复发，缓解症状，降低疾病的任何直接或间接病理学后果，预防转移，减缓疾病进展率，改善或减轻疾病状态，及消退或改善的预后。术语“有效量”意指(i)治疗特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本公开化合物的用量。构成“治疗有效量”的活性物质(例如本公开的抗体或其抗原结合片段)的量可根据一些因素而变化，诸如个体的疾病状态、年龄、性别和重量，以及治疗剂或治疗剂组合在个体中引发所需应答的能力。有效量也可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
如本文所用，“第一治疗阶段”即初始治疗阶段，可以是诱导治疗阶段，“第二治疗阶段”即初始治疗阶段之后的治疗阶段，可以是维持治疗阶段。
术语“施用”或“给予”表示，使用本领域技术人员已知的多种方法和递送系统中的任一种，向主体物理引入包含治疗剂的组合物。
抗体或其抗原结合片段(例如，抗TIM-3抗体或其抗原结合片段或抗PD-1抗体或其抗原结合片段)的施用途径包括静脉内、肌肉内、皮下、腹膜内、脊柱或其它胃肠外施用途径，例如通过注射或输注。本文中使用的短语“胃肠外施用”是指，通常通过注射进行的非肠内施用的施用模式，且包括但不限于，静脉内、肌肉内、动脉内、鞘内、淋巴管内、病灶内、囊内、眶内、心内、真皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下、脊柱内、硬膜外和胸骨内注射和输注、以及体内电穿孔。还可以执行施用，例如，一次、多次，和/或在一个或多个延长的时间段中。
术语“统一剂量(flat dose)”的应用是指，不考虑患者的重量或体表面积(BSA)施用给患者的剂量。因此将统一剂量规定为药剂(例如，抗TIM-3抗体或其抗原结合片段或抗PD-1抗体或其抗原结合片段)的绝对量，而不是规定为mg/kg剂量。例如，60kg人和100kg人将接受相同剂量的抗体(例如，1200mg或1500mg抗TIM-3抗体或其抗原结合片段；又例如，200mg抗PD-1抗体或其抗原结合片段)。
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
在本文中，术语“受试者”、“患者”或“主体”可互换使用。在一些实施方案中，受试者、患者或主体是哺乳动物。在部分实施方案中，受试者、患者或主体是小鼠。在部分实施方案中，受试者、患者或主体是人。
如本文所用，“约”表示在本领域普通技术人员判定的对特定值可以接受的误差范围内，其部分取决于如何测量或测定该值，即测量系统的限制。例如，“约”按照本领域实践可表示1倍或超过1倍标准偏差以内。或者，“约”可以表示多至±5％的范围，例如在所给定的具体数值范围±2％范围内、±1％范围内或±0.5％范围内波动。当本公开或权利要求中给出特定值时，除非另有说明，“约”的含义应认为是在该特定值的可接受的误差范围内。在本文中，除非另有说明，所有药物的剂量、时间、步骤参数或条件的值默认均由“约”修饰。
如本文所用，“联用”或“联合使用”意指两种或更多种活性物质可以各自作为单一制剂同时地、或各自作为单一制剂以任何顺序依次地施用于受试者。或者，所述活性物质的全部配制在单一制剂中，同时施用于受试者。或者，所述活性物质的部分配制在单一制剂中、且所述活性物质中的其他部分各自作为单一制剂，同时地、或以任何顺序依次地施用于受试者。
术语“单剂量”是指含有一定量药品的最小包装单元，例如一盒药有七粒药片，则一粒药片为单剂量；或者一瓶注射液为单剂量。术语“多剂量”由多个单剂量组成。
术语“单位剂量”是指含有一定量药品的最小包装单元中所含的活性成分的剂量，例如，一瓶抗体注射液中所含的抗体的剂量为单位剂量。
在本文中，术语“药物组合物”和“制剂”具有相同的含义，并可互换使用。
术语“复发性”癌症是在对初始治疗(例如手术)产生应答后，在初始部位或远处部位再生的癌症。
术语“转移性”癌症是指从身体的一部分(例如鼻咽腔)扩散到身体的另一部分的癌症。
如本文所用，“治疗失败”定义为在治疗过程中或末次治疗后出现疾病进展或复发。
如本文所用，某“线治疗”是指患者接受不同药物或其他治疗的顺序中的一个位置。术语“一线治疗”是指是指根据患者病情可以首先选择或者标准选择的药物进行治疗。
词语“包括(comprise)”、“含有(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。
在本文中，除非上下文另有明确规定，否则单数术语涵盖复数指代物，反之亦然。
为了描述和公开的目的，以引用的方式将所有的专利、专利申请和其它已确定的出版物在此明确地并入本文。这些出版物仅因为它们的公开早于本公开的申请日而提供。所有关于这些文件的日期的声明或这些文件的内容的表述是基于申请者可得的信息，并且不构成任何关于这些文件的日期或这些文件的内容的正确性的承认。而且，在任何国家，在本中对这些出版物的任何引用并不构成关于该出版物成为本领域的公知常识的一部分的认可。
本公开还提供了以下一些具体的实施方案，但本公开的保护范围不限于此：
实施方案1.一种药物组合，其包括抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段，其中，所述抗TIM-3抗体或其抗原结合片段包含：
(1)SEQ ID NO:1所示氨基酸序列的HCDR1，SEQ ID NO:2所示氨基酸序列的HCDR2，SEQ ID NO:3所示氨基酸序列的HCDR3，SEQ ID NO:4所示氨基酸序列的LCDR1，SEQ ID NO:5所示氨基酸序列的LCDR2，和SEQ ID NO:6所示氨基酸序列的LCDR3；或
(2)SEQ ID NO:21所示氨基酸序列的HCDR1，SEQ ID NO:22所示氨基酸序列的HCDR2，SEQ ID NO:23所示氨基酸序列的HCDR3，SEQ ID NO:24所示氨基酸序列的LCDR1，SEQ ID NO:25所示氨基酸序列的LCDR2，和SEQ ID NO:26所示氨基酸序列的LCDR3。
实施方案2.根据实施方案1所述的药物组合，其中，所述抗TIM-3抗体或其抗原结合片段包含：
(1)氨基酸序列与SEQ ID NO:7所示氨基酸序列具有至少95％同一性的重链可变区，和氨基酸序列与SEQ ID NO:8所示氨基酸序列具有至少95％同一性的轻链可变区；或
(2)氨基酸序列与SEQ ID NO:27所示氨基酸序列具有至少95％同一性的重链可变区，和氨基酸序列与SEQ ID NO:28所示氨基酸序列具有至少95％同一性的轻链可变区。
实施方案3.根据实施方案1或2所述的药物组合，其中，所述抗TIM-3抗体或其抗原结合片段包含：
(1)氨基酸序列与SEQ ID NO:9所示氨基酸序列具有至少95％同一性的重链，和氨基酸序列与SEQ ID NO:10所示氨基酸序列具有至少95％同一性的轻链；或
(2)氨基酸序列与SEQ ID NO:29所示氨基酸序列具有至少95％同一性的重链，和氨基酸序列与SEQ ID NO:30所示氨基酸序列具有至少95％同一性的轻链。
实施方案4.根据实施方案1-3中任一项所述的药物组合，其中，所述抗TIM-3抗体或其抗原结合片段的单位剂量为60-1800mg、100-1600mg、120-1600mg、180-1200mg、或240-600mg；优选地，所述抗TIM-3抗体或其抗原结合片段的单位剂量为240mg、300mg、360mg和/或600mg。
实施方案5.根据实施方案1-4中任一项所述的药物组合，其中，所述抗PD-1抗体或其抗原结合片段的单位剂量为10-500mg、50-500mg、50-200mg、或100-200mg；优选地，所述抗PD-1抗体或其抗原结合片段的单位剂量为100mg和/或200mg。
实施方案6.根据实施方案1-5中任一项所述的药物组合，其中，所述抗TIM-3抗体或其抗原结合片段:抗PD-1抗体或其抗原结合片段的质量比为(0.1-180):1、(0.2-50):1、(0.5-9):1、(3-7.5):1、(4-7.5):1或(6-7.5):1。
实施方案7.根据实施方案1-6中任一项所述的药物组合，其中，所述药物组合适用于在单个治疗周 期内施用，其包括100-1800mg、600-1800mg、600-1500mg、或1200-1500mg的抗TIM-3抗体或其抗原结合片段；优选地，所述药物组合适用于在单个治疗周期内施用，其包括1200mg或1500mg的抗TIM-3抗体或其抗原结合片段；更优选地，所述药物组合适用于在单个治疗周期内施用，其包括1200mg的抗TIM-3抗体或其抗原结合片段。
实施方案8.根据实施方案7所述的药物组合，其中，所述药物组合还包括10-800mg、50-500mg、或100-200mg的抗PD-1抗体或其抗原结合片段；优选地，所述药物组合还包括200mg的抗PD-1抗体或其抗原结合片段。
实施方案9.根据实施方案1-8中任一项所述的药物组合，其中，所述抗PD-1抗体或其抗原结合片段包含：SEQ ID NO:11所示氨基酸序列的HCDR1，SEQ ID NO:12所示氨基酸序列的HCDR2，SEQ ID NO:13所示氨基酸序列的HCDR3，SEQ ID NO:14所示氨基酸序列的LCDR1，SEQ ID NO:15所示氨基酸序列的LCDR2，和SEQ ID NO:16所示氨基酸序列的LCDR3。
实施方案10.根据实施方案1-9中任一项所述的药物组合，其中，所述抗PD-1抗体或其抗原结合片段包含：氨基酸序列与SEQ ID NO:17所示氨基酸序列具有至少95％同一性的重链可变区，和氨基酸序列与SEQ ID NO:18所示氨基酸序列具有至少95％同一性的轻链可变区。
实施方案11.根据实施方案1-10中任一项所述的药物组合，其中，所述抗PD-1抗体或其抗原结合片段包含：氨基酸序列与SEQ ID NO:19所示氨基酸序列具有至少95％同一性的重链，和氨基酸序列与SEQ ID NO:20所示氨基酸序列具有至少95％同一性的轻链。
实施方案12.根据实施方案1-11中任一项所述的药物组合，其中，所述抗TIM-3抗体或其抗原结合片段和/或抗PD-1抗体或其抗原结合片段配制为用于胃肠外途径施用的制剂，优选地，所述抗TIM-3抗体或其抗原结合片段和抗PD-1抗体和/或其抗原结合片段配制为用于静脉内、肌肉内或皮下施用的制剂。
实施方案13.根据实施方案1-12中任一项所述的药物组合，其中，所述抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段分开配制。
实施方案14.根据实施方案1-13中任一项所述的药物组合，其中，所述抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段配制在单一制剂中。
实施方案15.一种药物组合，其包括实施方案1-14中任一项所述的药物组合和化疗药物。
实施方案16.根据实施方案15所述的药物组合，其中，所述化疗药物为铂类抗肿瘤药物和/或抗代谢类抗肿瘤药物；
可选地，所述铂类抗肿瘤药物选自顺铂、卡铂、奈达铂、双环铂、吡铂、奥沙利铂、米铂、洛铂、乐铂、四硝酸三铂、菲铂或沙铂中的一种或者多种；
可选地，所述抗代谢类抗肿瘤药物选自阿糖胞苷、吉西他滨、阿扎胞苷、安西他滨中的一种或多种。
实施方案17.根据实施方案16所述的药物组合，其中，所述化疗药物为顺铂和吉西他滨。
实施方案18.根据实施方案17所述的药物组合，其中所述吉西他滨的单位剂量为0.2g和/或1.0g，所述顺铂的单位剂量为2.5mg、5mg、10mg、20mg、25mg、30mg、50mg和/或100mg。
实施方案19.根据实施方案17或18所述的药物组合，其中所述药物组合适用于在单个治疗周期内施用，所述吉西他滨的剂量为1.0-2.0g/m2，所述顺铂的剂量为40-80mg/m2或、40-75mg/m2。
实施方案20.实施方案1-14中任一项所述的药物组合在制备用于治疗受试者中肿瘤的药物中的用途。
实施方案21.根据实施方案20所述的用途，其中，所述肿瘤为实体瘤；可选地，所述实体瘤为鼻咽癌。
实施方案22.根据实施方案20或21所述的用途，其中，所述抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段，可同时、先后和/或交替给药。
实施方案23.根据实施方案22所述的用途，其中，所述抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段先后给药。
实施方案24.根据实施方案20-23中任一项所述的用途，其中，所述抗TIM-3抗体或其抗原结合片段每1周、每2周、每3周、或每4周施用一次；可选地，所述抗TIM-3抗体或其抗原结合片段每次以100-1800mg、600-1800mg、600-1500mg、或1200-1500mg的剂量施用；优选地，所述抗TIM-3抗体或其抗原结合片段每次以1200mg或1500mg的剂量施用；更优选地，所述抗TIM-3抗体或其抗原结合片段每次 以1200mg的剂量施用。
实施方案25.根据实施方案20-24中任一项所述的用途，其中，所述抗PD-1抗体或其抗原结合片段每1周、每2周、每3周、或每4周施用一次；可选地，所述抗PD-1抗体或其抗原结合片段每次以10-800mg、50-500mg、或100-200mg的剂量施用；优选地，所述抗PD-1抗体或其抗原结合片段每次以200mg的剂量施用。
实施方案26.实施方案15-19中任一项所述的药物组合在制备用于治疗受试者中肿瘤的药物中的用途。
实施方案27.根据实施方案26所述的用途，其中，所述肿瘤为实体瘤；可选地，所述实体瘤为鼻咽癌。
实施方案28.根据实施方案26或27所述的用途，其中，所述抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段、顺铂和吉西他滨，可同时、先后和/或交替给药。
实施方案29.根据实施方案26-28中任一项所述的用途，其中，所述抗TIM-3抗体或其抗原结合片段每1周、每2周、每3周、或每4周施用一次；可选地，所述抗TIM-3抗体或其抗原结合片段每次以100-1800mg、600-1800mg、600-1500mg、或1200-1500mg的剂量施用；优选地，所述抗TIM-3抗体或其抗原结合片段每次以1200mg或1500mg的剂量施用；更优选地，所述抗TIM-3抗体或其抗原结合片段每次以1200mg的剂量施用。
实施方案30.根据实施方案26-29中任一项所述的用途，其中，所述抗PD-1抗体或其抗原结合片段每1周、每2周、每3周、或每4周施用一次；可选地，所述抗PD-1抗体或其抗原结合片段每次以10-800mg、50-500mg、或100-200mg的剂量施用；优选地，所述抗PD-1抗体或其抗原结合片段每次以200mg的剂量施用。
实施方案31.根据实施方案26-30中任一项所述的用途，其中，所述顺铂每1周、每2周、每3周、或每4周施用一次；可选地，所述顺铂每次以40-80mg/m2、或40-75mg/m2的剂量施用；优选地，所述顺铂每次以40mg/m2、60mg/m2、75mg/m2、80mg/m2的剂量施用。
实施方案32.根据实施方案26-31中任一项所述的用途，其中，所述吉西他滨每1周、每2周、每3周、或每4周施用两次；可选地，所述吉西他滨每次以0.5-1.0g/m2的剂量施用；优选地，所述吉西他滨每次以0.5g/m2、0.75g/m2或1.0g/m2的剂量施用。
实施方案33.一种在受试者中治疗肿瘤的方法，其中，所述方法包括向受试者给予有效量的实施方案1-19中任一项所述的药物组合。
实施方案34.一种在受试者中治疗肿瘤的方法，其中，所述方法包括在第一治疗阶段向受试者给予有效量的实施方案15-19中任一项所述的药物组合，并且在第二治疗阶段向受试者给予有效量的实施方案1-14中任一项所述的药物组合。
实施方案35.根据实施方案34所述的方法，其中，所述第一治疗阶段的治疗周期包括1-14个治疗周期、2-12个治疗周期或2-10个治疗周期，优选为2-8个治疗周期，更优选为4-6个治疗周期。
实施方案36.根据实施方案33-35中任一项所述的方法，其中，所述肿瘤为实体瘤；可选地，所述实体瘤为鼻咽癌。
实施方案37.一种用于治疗肿瘤的试剂盒，其包含实施方案1-19中任一项所述的药物组合；可选地，所述肿瘤为实体瘤；可选地，所述实体瘤为鼻咽癌。
实施方案38.一种联用药物组合，其包括：
a)实施方案15-19中任一项所述的药物组合，其被制备为适合在第一治疗阶段施用；和
b)实施方案1-14中任一项所述的药物组合，其被制备为适合在第二治疗阶段施用。
实施方案39.根据实施方案38所述的联用药物组合，其中，所述第一治疗阶段的治疗周期包括1-14个治疗周期、2-12个治疗周期或2-10个治疗周期，优选为2-8个治疗周期，更优选为4-6个治疗周期。
实施方案40.实施方案39所述的联用药物组合在制备用于治疗受试者中肿瘤的药物中的用途。
实施方案41.根据实施方案40所述的用途，其中，所述肿瘤为实体瘤；可选地，所述实体瘤为鼻咽癌。
实施例
为清楚起见，进一步用实施例来阐述本公开，但是实施例并非限制本公开的范围。本公开所使用的所有试剂是市售的，无需进一步纯化即可使用。
WO2020041520或CN112566936A专利申请文件的全部内容均引入本公开。下述实施例中抗TIM-3抗体的重链氨基酸序列如本公开的SEQ ID NO:9所示，轻链氨基酸序列如本公开的SEQ ID NO:10所示。
CN106977602A专利申请文件的全部内容均引入本公开。下述实施例中抗PD-1抗体的重链氨基酸序列如本公开的SEQ ID NO:19所示，轻链氨基酸序列如本公开的SEQ ID NO:20所示。
实施例1：鼻咽癌的临床试验
1.入选标准
满足以下所有入选标准者才能入组本试验：
(1)受试者自愿加入本研究，签署知情同意书(ICF)；
(2)年龄：入组队列1的受试者：18-75周岁(签署ICF时)，入组队列2的受试者：18-70周岁(签署ICF时)；ECOG PS评分：0-1分；预计生存期超过3个月；
(3)入组患者符合下列标准：经组织学或细胞学证实为鼻咽癌，按照2017年第8版AJCC鼻咽癌TNM分期系统定义的IVb期或不适合局部治疗的复发性鼻咽癌受试者(对于新辅助/辅助治疗、根治性同步放化疗，如果在治疗期间或停止治疗后6个月内疾病进展，应算作原方案一线治疗失败，如果超过6个月，则不能算作一线治疗失败。所有因药物不耐受而改变治疗方案的不算做治疗失败)：
队列1入组的患者还需满足：
1)应至少接受过针对复发/转移灶的一线治疗，且入组前最后一次抗肿瘤治疗有符合RECIST 1.1标准的影像学进展证据；
2)既往至少接受过含铂化疗和免疫检查点抑制剂(抗PD-1单抗/抗PD-L1单抗等)治疗失败且有符合RECIST 1.1标准的影像学进展证据，含铂化疗和免疫治疗可在针对复发/转移灶的姑息性治疗期间，也可在针对局部晚期疾病的根治性治疗期间；
3)针对复发/转移灶的免疫治疗不超过2线，(对于新辅助/辅助治疗、根治性同步放化疗，如果在治疗期间或停止治疗后6个月内疾病进展，应算作原方案一线治疗失败，如果超过6个月，则不能算作一线治疗失败。所有因药物不耐受而改变治疗方案的不算做治疗失败)；
4)距离入组前最近的一次免疫治疗，如针对复发/转移灶，则最佳疗效至少为SD(≥6周)或确认的PR或免疫治疗持续时间≥12周。
队列2入组的患者还需满足：
1)既往未接受针对复发/转移性鼻咽癌的全身系统性抗肿瘤治疗；
2)既往未接受过免疫检查点抑制剂(抗PD-1单抗/抗PD-L1单抗等)的治疗。在局部晚期根治性治疗阶段使用过不超过一种免疫检查点抑制剂(限抗CTLA-4/PD-1/PD-L1单抗)者，如符合如下标准可纳入：
a)如在诱导阶段使用过(联合或不联合其他药物治疗)，诱导阶段最佳疗效至少为PR；
b)如在根治性放化疗/放疗期间或后续维持阶段使用过，在治疗期间以及停止治疗后6个月内无影像或明显临床进展，且发现疾病进展的时间距离完成根治性放(化)疗超过一年。
(4)根据RECIST 1.1标准证实具有至少一个可测量病灶；
(5)主要器官功能正常，即符合下列标准：
1)血常规检查标准(检查前14天内未输血、未使用造血刺激因子类药物纠正)：
a.血红蛋白(HGB)≥90g/L；
b.中性粒细胞绝对值(NEUT)≥1.5×109/L；
c.血小板计数(PLT)≥100×109/L；
2)生化检查需符合以下标准：
a.总胆红素(TBIL)≤1.5倍正常值上限(ULN)(Gilbert综合症患者：TBIL≤3×ULN)；
b.丙氨酸氨基转移酶(ALT)和天门冬氨酸氨基转移酶(AST)≤2.5×ULN(原发肝胆肿瘤或肿瘤肝脏转移者：ALT、AST≤5×ULN)；
c.血清肌酐(CR)≤1.5×ULN或肌酐清除率(CCR)≥60mL/min；
3)凝血功能需符合以下标准：
活化部分凝血酶时间(APTT)、国际标准化比值(INR)、凝血酶原时间(PT)≤1.5×ULN(未接受过抗凝治疗)；
4)甲状腺功能检查需符合以下标准：
促甲状腺激素(TSH)≤ULN；如果异常应考察T3和T4水平，三碘甲状腺原氨酸(T3)和四碘甲状腺原氨酸(T4)水平正常则可以入选。
5)心脏彩超评估：左室射血分数(LVEF)≥50％。
(6)育龄女性受试者应同意在研究期间和研究结束后6个月内必须采用避孕措施(如宫内节育器、避孕药或避孕套)；在研究入组前的7天内血清妊娠/尿妊娠试验阴性，且必须为非哺乳期受试者；男性受试者应同意在研究期间和研究期结束后6个月内必须采用避孕措施。
2.试验药物
先进行抗PD-1抗体注射液输注，再进行抗TIM-3抗体注射液输注。
2.1抗PD-1抗体注射液(规格：100mg/10mL/瓶)：每3周为1个治疗周期(给药时间窗：±3天)，通过静脉输注，每个治疗周期第1天以200mg抗PD-1抗体的剂量给药一次(即200mg，d1/Q3W)。
2.2抗TIM-3抗体注射液(规格：240mg/4mL/瓶、或600mg/10mL/瓶)：每3周为1个治疗周期(给药时间窗：±3天)，通过静脉输注，每个治疗周期第1天以1200mg或1500mg抗TIM-3抗体的剂量给药一次(即1200mg或1500mg，d1/Q3W)。
2.3盐酸吉西他滨注射液：起始剂量1g/m2，每个治疗周期第1天和第8天给药。
2.4顺铂注射液：起始剂量75mg/m2，每个治疗周期第1天给药。
3.治疗方案
3.1队列1：抗TIM-3抗体注射液(1200mg或1500mg，d1/Q3W)+抗PD-1抗体注射液(200mg，d1/Q3W)。
3.2队列2：抗TIM-3抗体注射液(1200mg，d1/Q3W)+抗PD-1抗体注射液(200mg，d1/Q3W)+GP化疗方案(吉西他滨+顺铂)诱导治疗4-6个治疗周期后，抗TIM-3抗体注射液(1200mg，d1/Q3W)+抗PD-1抗体注射液(200mg，d1/Q3W)维持治疗。
4.评价标准
疗效评估标准依据RECIST 1.1，同时使用iRECIST标准对疗效进行确认。
5.终点指标
客观缓解率(ORR)、完全缓解率(CRR)、疾病控制率(DCR)、缓解持续时间(DOR)、无进展生存期(PFS)、总生存期(OS)等；
不良事件发生率：所有不良事件(AE)、严重不良事件(SAE)和治疗相关不良事件(TRAEs)的发生情况，以及异常实验室检查指标。
6.结果
初步研究显示，本公开的药物组合可以安全、有效地治疗鼻咽癌，尤其是晚期、复发和/或转移性鼻咽癌。
队列1中，经3.1的治疗方案治疗后，免疫检查点抑制剂治疗失败的晚期鼻咽癌患者病情得到有效缓解和控制。
队列2中，经3.2的治疗方案后，复发性/转移性鼻咽癌患者病情得到有效缓解和控制。截止数据统计日，有13例可评估患者，其中，9例患者观察到部分反应(PR)，4例患者表现出疾病稳定(SD)，ORR达到69.2％，DCR为100％。队列2的示例性患者的具体情况如下所示。
(1)患者001
被诊断为：初治鼻咽未分化型非角化性癌，伴骨转移。既往未接受过鼻咽癌治疗。
经抗TIM-3抗体注射液+抗PD-1抗体注射液+GP化疗方案诱导治疗6个治疗周期，抗TIM-3抗体注射液+抗PD-1抗体注射液维持治疗。靶病灶大小和评估结果如下所示：
筛选期，靶病灶：34mm；
第2治疗周期给药后，靶病灶：28mm；
第4治疗周期给药后，靶病灶：25mm；
第6治疗周期给药后，靶病灶：21mm；
第8治疗周期给药后，靶病灶：22mm。
根据疗效评估标准，患者的最佳疗效为PR。
(2)患者002
被诊断为：初治鼻咽非角化性癌，伴肝、骨转移。既往未接受过鼻咽癌治疗。
经抗TIM-3抗体注射液+抗PD-1抗体注射液+GP化疗方案诱导治疗6个治疗周期，抗TIM-3抗体注射液+抗PD-1抗体注射液维持治疗。靶病灶大小和评估结果如下所示：
筛选期，靶病灶：41mm；
第2治疗周期给药后，靶病灶：28mm；
第4治疗周期给药后，靶病灶：19mm；
第6治疗周期给药后，靶病灶：17mm；
第8治疗周期给药后，靶病灶：18mm。
根据疗效评估标准，患者的最佳疗效为PR。
(3)患者003
被诊断为：初治鼻咽未分化型非角化性癌。既往未接受过鼻咽癌治疗。
经抗TIM-3抗体注射液+抗PD-1抗体注射液+GP化疗方案诱导治疗4个治疗周期，抗TIM-3抗体注射液+抗PD-1抗体注射液维持治疗。靶病灶大小和评估结果如下所示：
筛选期，靶病灶：30.5mm；
第2治疗周期给药后，靶病灶：20.3mm；
第4治疗周期给药后，靶病灶：19.4mm；
第6治疗周期给药后，靶病灶：19.2mm；
第8治疗周期给药后，靶病灶：15.3mm。
根据疗效评估标准，患者的最佳疗效为PR。
(4)患者004
被诊断为：鼻咽未分化型非角化性癌，伴肺转移。在局部晚期阶段接受过放疗与尼妥珠单抗的联合治疗。
经抗TIM-3抗体注射液+抗PD-1抗体注射液+GP化疗方案诱导治疗4个治疗周期。靶病灶大小和评估结果如下所示：
筛选期，靶病灶：35mm；
第2治疗周期给药后，靶病灶：15mm；
第4治疗周期给药后，靶病灶：14mm。
根据疗效评估标准，患者的最佳疗效为PR。
(5)患者005
被诊断为：初治鼻咽非角化性鳞状细胞癌(T2N3M1，IVb期)，伴肝、骨转移。既往未接受过鼻咽癌治疗。
经抗TIM-3抗体注射液+抗PD-1抗体注射液+GP化疗方案诱导治疗6个治疗周期，抗TIM-3抗体注射液+抗PD-1抗体注射液维持治疗。靶病灶大小和评估结果如下所示：
筛选期，靶病灶：112.36mm；
第2治疗周期给药后，靶病灶：77.2mm；
第4治疗周期给药后，靶病灶：66.4mm；
第6治疗周期给药后，靶病灶：65.2mm。
根据疗效评估标准，患者的最佳疗效为PR。
(6)患者006
被诊断为：初治鼻咽未分化型非角化性癌，伴双颈、腋窝多发淋巴结转移。既往未接受过鼻咽癌治疗。
经抗TIM-3抗体注射液+抗PD-1抗体注射液+GP化疗方案诱导治疗5个治疗周期。靶病灶大小和评估结果如下所示：
筛选期，靶病灶：39mm；
第2治疗周期给药后，靶病灶：19mm；
第4治疗周期给药后，靶病灶：13.5mm。
根据疗效评估标准，患者的最佳疗效为PR。
(7)患者007
被诊断为：鼻咽未分化型非角化性癌，伴纵隔、双肺门多发淋巴结转移。既往经GP化疗方案诱导化疗+放疗+抗PD-1抗体(信迪利单抗)+顺铂治疗。
经抗TIM-3抗体注射液+抗PD-1抗体注射液+GP化疗方案诱导治疗4个治疗周期。靶病灶大小和评估结果如下所示：
筛选期，靶病灶：17mm；
第2治疗周期给药后，靶病灶：11mm。
根据疗效评估标准，患者的最佳疗效为PR。
(8)患者008
被诊断为：初治鼻咽未分化型非角化性癌，伴肝转移。既往未接受过鼻咽癌治疗。
经抗TIM-3抗体注射液+抗PD-1抗体注射液+GP化疗方案诱导治疗4个治疗周期。靶病灶大小和评估结果如下所示：
筛选期，靶病灶：84mm；
第2治疗周期给药后，靶病灶：34mm。
根据疗效评估标准，患者的最佳疗效为PR。
(9)患者009
被诊断为：初治鼻咽未分化型非角化性癌鼻，伴骨转移。既往未接受过鼻咽癌治疗。
治疗方案：抗TIM-3抗体注射液+抗PD-1抗体注射液+GP化疗方案诱导治疗3个治疗周期。靶病灶大小和评估结果如下所示：
筛选期，靶病灶：53.4mm；
第2治疗周期给药后，靶病灶：19.7mm。
根据疗效评估标准，患者的最佳疗效为PR。

Claims (17)

  1. 一种药物组合，其包括抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段，其中，所述抗TIM-3抗体或其抗原结合片段包含：
    (1)SEQ ID NO:1所示氨基酸序列的HCDR1，SEQ ID NO:2所示氨基酸序列的HCDR2，SEQ ID NO:3所示氨基酸序列的HCDR3，SEQ ID NO:4所示氨基酸序列的LCDR1，SEQ ID NO:5所示氨基酸序列的LCDR2，和SEQ ID NO:6所示氨基酸序列的LCDR3；
    (2)SEQ ID NO:21所示氨基酸序列的HCDR1，SEQ ID NO:22所示氨基酸序列的HCDR2，SEQ ID NO:23所示氨基酸序列的HCDR3，SEQ ID NO:24所示氨基酸序列的LCDR1，SEQ ID NO:25所示氨基酸序列的LCDR2，和SEQ ID NO:26所示氨基酸序列的LCDR3；
    (3)氨基酸序列与SEQ ID NO:7所示氨基酸序列具有至少95％同一性的重链可变区，和氨基酸序列与SEQ ID NO:8所示氨基酸序列具有至少95％同一性的轻链可变区；
    (4)氨基酸序列与SEQ ID NO:27所示氨基酸序列具有至少95％同一性的重链可变区，和氨基酸序列与SEQ ID NO:28所示氨基酸序列具有至少95％同一性的轻链可变区；
    (5)氨基酸序列与SEQ ID NO:9所示氨基酸序列具有至少95％同一性的重链，和氨基酸序列与SEQ ID NO:10所示氨基酸序列具有至少95％同一性的轻链；或
    (6)氨基酸序列与SEQ ID NO:29所示氨基酸序列具有至少95％同一性的重链，和氨基酸序列与SEQ ID NO:30所示氨基酸序列具有至少95％同一性的轻链。
  2. 根据权利要求1所述的药物组合，其中，所述抗TIM-3抗体或其抗原结合片段的单位剂量为60-1800mg、100-1600mg、120-1600mg、180-1200mg、或240-600mg；优选地，所述抗TIM-3抗体或其抗原结合片段的单位剂量为240mg、300mg、360mg和/或600mg；
    可选地，所述抗PD-1抗体或其抗原结合片段的单位剂量为10-500mg、50-500mg、50-200mg、或100-200mg；优选地，所述抗PD-1抗体或其抗原结合片段的单位剂量为100mg和/或200mg。
  3. 根据权利要求1或2所述的药物组合，其中，所述抗TIM-3抗体或其抗原结合片段:抗PD-1抗体或其抗原结合片段的质量比为(0.1-180):1、(0.2-50):1、(0.5-9):1、(3-7.5):1、(4-7.5):1或(6-7.5):1。
  4. 根据权利要求1-3中任一项所述的药物组合，其中，所述药物组合适用于在单个治疗周期内施用，其包括100-1800mg、600-1800mg、600-1500mg、或1200-1500mg的抗TIM-3抗体或其抗原结合片段；优选地，所述药物组合适用于在单个治疗周期内施用，其包括1200mg或1500mg的抗TIM-3抗体或其抗原结合片段；
    可选地，所述药物组合还包括10-800mg、50-500mg、或100-200mg的抗PD-1抗体或其抗原结合片段；优选地，所述药物组合还包括200mg的抗PD-1抗体或其抗原结合片段。
  5. 根据权利要求1-4中任一项所述的药物组合，其中，所述抗PD-1抗体或其抗原结合片段包含：
    (1)SEQ ID NO:11所示氨基酸序列的HCDR1，SEQ ID NO:12所示氨基酸序列的HCDR2，SEQ ID NO:13所示氨基酸序列的HCDR3，SEQ ID NO:14所示氨基酸序列的LCDR1，SEQ ID NO:15所示氨基酸序列的LCDR2，和SEQ ID NO:16所示氨基酸序列的LCDR3；
    (2)氨基酸序列与SEQ ID NO:17所示氨基酸序列具有至少95％同一性的重链可变区，和氨基酸序列与SEQ ID NO:18所示氨基酸序列具有至少95％同一性的轻链可变区；或
    (3)氨基酸序列与SEQ ID NO:19所示氨基酸序列具有至少95％同一性的重链，和氨基酸序列与SEQ ID NO:20所示氨基酸序列具有至少95％同一性的轻链。
  6. 根据权利要求1-5中任一项所述的药物组合，其中，所述抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段分开配制或配制在单一制剂中。
  7. 一种药物组合，其包括权利要求1-6中任一项所述的药物组合和化疗药物；优选地，所述化疗药物为铂类抗肿瘤药物和/或抗代谢类抗肿瘤药物；
    可选地，所述铂类抗肿瘤药物选自顺铂、卡铂、奈达铂、双环铂、吡铂、奥沙利铂、米铂、洛铂、乐铂、四硝酸三铂、菲铂或沙铂中的一种或者多种；
    可选地，所述抗代谢类抗肿瘤药物选自阿糖胞苷、吉西他滨、阿扎胞苷、安西他滨中的一种或多种；
    可选地，所述化疗药物为顺铂和吉西他滨。
  8. 根据权利要求7所述的药物组合，其中所述吉西他滨的单位剂量为0.2g和/或1.0g，所述顺铂的单位剂量为2.5mg、5mg、10mg、20mg、25mg、30mg、50mg和/或100mg。
  9. 权利要求1-6中任一项所述的药物组合在制备用于治疗受试者中肿瘤的药物中的用途；优选地，所述肿瘤为实体瘤；更优选地，所述实体瘤为鼻咽癌。
  10. 根据权利要求9所述的用途，其中，所述抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段，可同时、先后和/或交替给药；优选地，所述抗TIM-3抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段先后给药。
  11. 权利要求7-8中任一项所述的药物组合在制备用于治疗受试者中肿瘤的药物中的用途；优选地，所述肿瘤为实体瘤；更优选地，所述实体瘤为鼻咽癌。
  12. 根据权利要求11所述的用途，其中，所述抗TIM-3抗体或其抗原结合片段、抗PD-1抗体或其抗原结合片段、顺铂和吉西他滨，可同时、先后和/或交替给药。
  13. 根据权利要求9-12中任一项所述的用途，其中，所述抗TIM-3抗体或其抗原结合片段每1周、每2周、每3周、或每4周施用一次；
    可选地，所述抗TIM-3抗体或其抗原结合片段每次以100-1800mg、600-1800mg、600-1500mg、或1200-1500mg的剂量施用；优选地，所述抗TIM-3抗体或其抗原结合片段每次以1200mg或1500mg的剂量施用；
    可选地，所述抗PD-1抗体或其抗原结合片段每1周、每2周、每3周、或每4周施用一次；
    可选地，所述抗PD-1抗体或其抗原结合片段每次以10-800mg、50-500mg、或100-200mg的剂量施用；优选地，所述抗PD-1抗体或其抗原结合片段每次以200mg的剂量施用。
  14. 根据权利要求11-13中任一项所述的用途，其中，所述顺铂每1周、每2周、每3周、或每4周施用一次；
    可选地，所述顺铂每次以40-80mg/m2或40-75mg/m2的剂量施用；优选地，所述顺铂每次以40mg/m2、60mg/m2、75mg/m2、80mg/m2顺铂的剂量施用；
    可选地，所述吉西他滨每1周、每2周、每3周、或每4周施用两次；
    可选地，所述吉西他滨每次以0.5-1.0g/m2的剂量施用；优选地，所述吉西他滨每次以0.5g/m2、0.75g/m2或1.0g/m2的剂量施用。
  15. 一种在受试者中治疗肿瘤的方法，其中，所述方法包括向受试者给予有效量的权利要求1-8中任一项所述的药物组合；或者，所述方法包括在第一治疗阶段向受试者给予有效量的权利要求7-8中任一项所述的药物组合，并且在第二治疗阶段向受试者给予有效量的权利要求1-6中任一项所述的药物组合；
    可选地，所述第一治疗阶段的治疗周期为1-14个治疗周期、2-12个治疗周期或2-10个治疗周期，优选为2-8个治疗周期，更优选为4-6个治疗周期；
    可选地，所述肿瘤为实体瘤；优选地，所述实体瘤为鼻咽癌。
  16. 一种联用药物组合，其包括：
    (a)权利要求7-8中任一项所述的药物组合，其被制备为适合在第一治疗阶段施用；和
    (b)权利要求1-6中任一项所述的药物组合，其被制备为适合在第二治疗阶段施用；
    可选地，所述第一治疗阶段的治疗周期为1-14个治疗周期、2-12个治疗周期或2-10个治疗周期，优选2-8个治疗周期，更优选为4-6个治疗周期。
  17. 权利要求16所述的联用药物组合在制备用于治疗受试者中肿瘤的药物中的用途；优选地，所述肿瘤为实体瘤；更优选地，所述实体瘤为鼻咽癌。
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